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				<span dir="auto">Insulin</span>
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				<div lang="en" dir="ltr" class="mw-content-ltr"><div class="dablink">This article is about the insulin protein.  For uses of insulin in treating diabetes, see <a href="/wiki/Insulin_therapy" title="Insulin therapy">insulin therapy</a>.</div>
<div class="dablink">Not to be confused with <a href="/wiki/Inulin" title="Inulin">inulin</a>.</div>
<table class="infobox" cellspacing="5" style="width: 22em; text-align: left; font-size: 88%; line-height: 1.5em;">
<tr class="">
<th colspan="4" style="text-align:center; text-align:center; font-size:125%; font-weight:bold;">Insulin</th>
</tr>
<tr class="">
<td colspan="4" class="" style="text-align:center;"><a href="/wiki/File:InsulinHexamer.jpg" class="image"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/0/0d/InsulinHexamer.jpg/250px-InsulinHexamer.jpg" width="250" height="262" /></a><br />
<span style="">Computer-generated image of six insulin molecules assembled in a hexamer, highlighting the threefold <a href="/wiki/Symmetry" title="Symmetry">symmetry</a>, the <a href="/wiki/Zinc" title="Zinc">zinc</a> ions holding it together, and the <a href="/wiki/Histidine" title="Histidine">histidine</a> residues involved in zinc binding. Insulin is stored in the body as a hexamer, while the active form is the monomer. <sup id="cite_ref-pmid9235985_0-0" class="reference"><a href="#cite_note-pmid9235985-0"><span>[</span>1<span>]</span></a></sup></span></td>
</tr>
<tr class="">
<td colspan="4" class="" style="text-align:center; background-color: #eee">
<table class="collapsible collapsed" style="border: none; padding: 0; margin: 0; width: 100%; text-align: left">
<tr style="background-color: #ddd; text-align: center">
<th colspan="2">Available structures</th>
</tr>
<tr>
<th style="background-color: #c3fdb8; width:43px"><a href="/wiki/Protein_Data_Bank" title="Protein Data Bank">PDB</a></th>
<td style="background-color: #eee"><a rel="nofollow" class="external text" href="http://www.ebi.ac.uk/pdbe/searchResults.html?display=both&amp;term=O73727%20or%20P01308%20or%20P01315%20or%20P01317%20or%20P01321%20or%20P01323%20or%20P01326%20or%20P30410%20or%20P67970">PDBe</a> <a rel="nofollow" class="external text" href="http://www.rcsb.org/pdb/search/smartSubquery.do?smartSearchSubtype=UpAccessionIdQuery&amp;accessionIdList=O73727,P01308,P01315,P01317,P01321,P01323,P01326,P30410,P67970">RCSB</a></td>
</tr>
</table>
</td>
</tr>
<tr class="">
<th colspan="4" style="text-align:center; background-color: #ddd">Identifiers</th>
</tr>
<tr class="">
<th style="background-color: #c3fdb8"><a href="/wiki/Human_Genome_Organisation" title="Human Genome Organisation">Symbols</a></th>
<td colspan="3" class="" style="background-color: #eee"><span class="plainlinks"><a rel="nofollow" class="external text" href="http://www.genenames.org/data/hgnc_data.php?hgnc_id=6081">INS</a>;</span></td>
</tr>
<tr class="">
<th style="background-color: #c3fdb8">External IDs</th>
<td colspan="3" class="" style="background-color: #eee"><span class="plainlinks"><a href="/wiki/Mendelian_Inheritance_in_Man" title="Mendelian Inheritance in Man" class="mw-redirect">OMIM</a>:&#160;<a rel="nofollow" class="external text" href="http://omim.org/entry/176730">176730</a></span> <span class="plainlinks"><a href="/wiki/Mouse_Genome_Informatics" title="Mouse Genome Informatics">MGI</a>:&#160;<a rel="nofollow" class="external text" href="http://www.informatics.jax.org/searches/accession_report.cgi?id=MGI:96573">96573</a></span> <span class="plainlinks"><a href="/wiki/HomoloGene" title="HomoloGene">HomoloGene</a>:&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=homologene&amp;dopt=HomoloGene&amp;list_uids=173">173</a></span> <a href="/wiki/GeneCards" title="GeneCards">GeneCards</a>: <span class="plainlinks"><a rel="nofollow" class="external text" href="http://www.genecards.org/cgi-bin/carddisp.pl?id_type=entrezgene&amp;id=3630">INS Gene</a></span></td>
</tr>
<tr class="">
<td colspan="4" class="" style="text-align:center; background-color: #eee">
<table class="collapsible collapsed" style="border: none; padding: 0; margin: 0; width: 100%; text-align: left">
<tr style="background-color: #ddd; text-align: center">
<th colspan="2"><a href="/wiki/Gene_Ontology" title="Gene Ontology">Gene Ontology</a></th>
</tr>
<tr>
<th style="background-color: #c3fdb8">Molecular function</th>
<td style="background-color: #eee"><big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0005158">insulin receptor binding</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0005179">hormone activity</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0005515">protein binding</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0005520">insulin-like growth factor binding</a></span><br /></td>
</tr>
<tr>
<th style="background-color: #c3fdb8">Cellular component</th>
<td style="background-color: #eee"><big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0005576">extracellular region</a></span><br /></td>
</tr>
<tr>
<th style="background-color: #c3fdb8">Biological process</th>
<td style="background-color: #eee"><big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0005975">carbohydrate metabolic process</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0006006">glucose metabolic process</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0006091">generation of precursor metabolites and energy</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0006953">acute-phase response</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0007166">cell surface receptor linked signal transduction</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0007267">cell-cell signaling</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0008219">cell death</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0015758">glucose transport</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0042177">negative regulation of protein catabolic process</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0045429">positive regulation of nitric oxide biosynthetic process</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0045908">negative regulation of vasodilation</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0045909">positive regulation of vasodilation</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0046631">alpha-beta T cell activation</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0050708">regulation of protein secretion</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0050715">positive regulation of cytokine secretion</a></span><br />
<big>•</big> <span class="plainlinks"><a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/go.cgi?view=details&amp;search_constraint=terms&amp;depth=0&amp;query=GO:0051000">positive regulation of nitric-oxide synthase activity</a></span><br /></td>
</tr>
<tr>
<td style="background-color: #eee;text-align:center;" colspan="2">Sources: <a rel="nofollow" class="external text" href="http://amigo.geneontology.org/cgi-bin/amigo/gp-assoc.cgi?gp=UniProtKB:P01308">Amigo</a> / <a rel="nofollow" class="external text" href="http://www.ebi.ac.uk/QuickGO/GProtein?ac=P01308">QuickGO</a></td>
</tr>
</table>
</td>
</tr>
<tr class="">
<th colspan="4" style="text-align:center; background-color: #ddd">RNA expression pattern</th>
</tr>
<tr class="">
<td colspan="4" class="" style="text-align:center; background-color: #eee"><a href="/wiki/File:PBB_GE_INS_206598_at_tn.png" class="image"><img alt="PBB GE INS 206598 at tn.png" src="//upload.wikimedia.org/wikipedia/commons/thumb/3/3f/PBB_GE_INS_206598_at_tn.png/250px-PBB_GE_INS_206598_at_tn.png" width="250" height="132" /></a></td>
</tr>
<tr class="">
<td colspan="4" class="" style="text-align:center; background-color: #eee"><span class="plainlinks"><a rel="nofollow" class="external text" href="http://biogps.org/gene/3630/">More reference expression data</a></span></td>
</tr>
<tr class="">
<th colspan="4" style="text-align:center; background-color: #ddd">Orthologs</th>
</tr>
<tr class="" style="">
<th style="background-color: #c3fdb8">Species</th>
<td class="" style=""><b>Human</b></td>
<td class="" style=""><b>Mouse</b></td>
<td class="" style=""></td>
</tr>
<tr class="" style="">
<th style="background-color: #c3fdb8"><a href="/wiki/Entrez" title="Entrez">Entrez</a></th>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&amp;cmd=retrieve&amp;dopt=default&amp;list_uids=3630&amp;rn=1">3630</a></span></td>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&amp;cmd=retrieve&amp;dopt=default&amp;list_uids=16334&amp;rn=1">16334</a></span></td>
<td class="" style=""></td>
</tr>
<tr class="" style="">
<th style="background-color: #c3fdb8"><a href="/wiki/Ensembl" title="Ensembl">Ensembl</a></th>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external text" href="http://www.ensembl.org/Homo_sapiens/geneview?gene=ENSG00000129965;db=core">ENSG00000129965</a></span></td>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external text" href="http://www.ensembl.org/Mus_musculus/geneview?gene=ENSMUSG00000000215;db=core">ENSMUSG00000000215</a></span></td>
<td class="" style=""></td>
</tr>
<tr class="" style="">
<th style="background-color: #c3fdb8"><a href="/wiki/UniProt" title="UniProt">UniProt</a></th>
<td class="" style=""><span class="plainlinks"><a rel="nofollow" class="external text" href="http://www.uniprot.org/uniprot/P01308">P01308</a></span></td>
<td class="" style=""><span class="plainlinks"><a rel="nofollow" class="external text" href="http://www.uniprot.org/uniprot/Q5EEX1">Q5EEX1</a></span></td>
<td class="" style=""></td>
</tr>
<tr class="" style="">
<th style="background-color: #c3fdb8">RefSeq (mRNA)</th>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_000207">NM_000207</a></span></td>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NM_008387">NM_008387</a></span></td>
<td class="" style=""></td>
</tr>
<tr class="" style="">
<th style="background-color: #c3fdb8">RefSeq (protein)</th>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_000198">NP_000198</a></span></td>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?val=NP_032413">NP_032413</a></span></td>
<td class="" style=""></td>
</tr>
<tr class="" style="">
<th style="background-color: #c3fdb8">Location (UCSC)</th>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external text" href="http://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&amp;db=hg18&amp;position=chr11:2137585-2139147">Chr 11:<br />
2.14 – 2.14 Mb</a></span></td>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external text" href="http://genome.ucsc.edu/cgi-bin/hgTracks?org=Mouse&amp;db=mm8&amp;position=chr7:142488051-142489098">Chr 7:<br />
142.49 – 142.49 Mb</a></span></td>
<td class="" style=""></td>
</tr>
<tr class="" style="">
<th style="background-color: #c3fdb8"><a href="/wiki/PubMed" title="PubMed">PubMed</a> search</th>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external autonumber" href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&amp;cmd=Link&amp;LinkName=gene_pubmed&amp;from_uid=3630">[1]</a></span></td>
<td class="" style=""><span class="plainlinks" style="white-space: nowrap"><a rel="nofollow" class="external autonumber" href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&amp;cmd=Link&amp;LinkName=gene_pubmed&amp;from_uid=16334">[2]</a></span></td>
<td class="" style=""></td>
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<p><b>Insulin</b> is a <a href="/wiki/Hormone" title="Hormone">hormone</a> produced by the <a href="/wiki/Pancreas" title="Pancreas">pancreas</a> which is central to regulating <a href="/wiki/Carbohydrate" title="Carbohydrate">carbohydrate</a> and <a href="/wiki/Fat" title="Fat">fat</a> metabolism in the body. Insulin causes cells in the <a href="/wiki/Liver" title="Liver">liver</a>, <a href="/wiki/Muscle" title="Muscle">muscle</a>, and <a href="/wiki/Fat_cell" title="Fat cell" class="mw-redirect">fat tissue</a> to take up <a href="/wiki/Glucose" title="Glucose">glucose</a> from the <a href="/wiki/Blood" title="Blood">blood</a>, storing it as <a href="/wiki/Glycogen" title="Glycogen">glycogen</a> in the liver and muscle.</p>
<p>Insulin stops the use of fat as an energy source by inhibiting the release of <a href="/wiki/Glucagon" title="Glucagon">glucagon</a>. With the exception of the metabolic disorder <a href="/wiki/Diabetes_mellitus" title="Diabetes mellitus">diabetes mellitus</a> and Metabolic syndrome, insulin is provided within the body in a constant proportion to remove excess glucose from the blood, which otherwise would be toxic. When blood glucose levels fall below a certain level, the body begins to use stored sugar as an energy source through <a href="/wiki/Glycogenolysis" title="Glycogenolysis">glycogenolysis</a>, which breaks down the glycogen stored in the liver and muscles into glucose, which can then be utilized as an energy source. As its level is a central metabolic control mechanism, its status is also used as a control signal to other body systems (such as <a href="/wiki/Amino_acid" title="Amino acid">amino acid</a> uptake by body cells). In addition, it has several other <a href="/wiki/Anabolism" title="Anabolism">anabolic</a> effects throughout the body.</p>
<p>When control of insulin levels fails, <a href="/wiki/Diabetes_mellitus" title="Diabetes mellitus">diabetes mellitus</a> will result. As a consequence, insulin is used medically to treat some forms of diabetes mellitus. Patients with <a href="/wiki/Diabetes_mellitus_type_1" title="Diabetes mellitus type 1">type 1 diabetes</a> depend on external insulin (most commonly <a href="/wiki/Subcutaneous_injection" title="Subcutaneous injection">injected subcutaneously</a>) for their survival because the hormone is no longer produced internally. Patients with <a href="/wiki/Diabetes_mellitus_type_2" title="Diabetes mellitus type 2">type 2 diabetes</a> are often <a href="/wiki/Insulin_resistance" title="Insulin resistance">insulin resistant</a> and, because of such resistance, may suffer from a "relative" insulin deficiency. Some patients with type 2 diabetes may eventually require insulin if other medications fail to control blood glucose levels adequately. Over 40% of those with Type 2 diabetes require insulin as part of their diabetes management plan.</p>
<p>Insulin also influences other body functions, such as <a href="/wiki/Compliance_(physiology)#Blood_vessels" title="Compliance (physiology)">vascular compliance</a> and <a href="/wiki/Cognition" title="Cognition">cognition</a>. Once insulin enters the human brain, it enhances learning and memory and benefits verbal memory in particular.<sup id="cite_ref-pmid15288712_1-0" class="reference"><a href="#cite_note-pmid15288712-1"><span>[</span>2<span>]</span></a></sup> Enhancing brain insulin signaling by means of intranasal insulin administration also enhances the acute thermoregulatory and glucoregulatory response to food intake, suggesting that central nervous insulin contributes to the control of whole-body energy homeostasis in humans.<sup id="cite_ref-pmid20876713_2-0" class="reference"><a href="#cite_note-pmid20876713-2"><span>[</span>3<span>]</span></a></sup></p>
<p>Human insulin is a <a href="/wiki/Peptide_hormone" title="Peptide hormone">peptide hormone</a> composed of 51 <a href="/wiki/Amino_acid" title="Amino acid">amino acids</a> and has a <a href="/wiki/Molecular_weight" title="Molecular weight" class="mw-redirect">molecular weight</a> of 5808 <a href="/wiki/Dalton_(unit)" title="Dalton (unit)" class="mw-redirect">Da</a>. It is produced in the <a href="/wiki/Islets_of_Langerhans" title="Islets of Langerhans">islets of Langerhans</a> in the pancreas. The name comes from the <a href="/wiki/Latin" title="Latin">Latin</a> <i>insula</i> for "island". Insulin's structure varies slightly between <a href="/wiki/Species" title="Species">species</a> of animals. Insulin from animal sources differs somewhat in "strength" (in <a href="/wiki/Carbohydrate_metabolism" title="Carbohydrate metabolism">carbohydrate metabolism</a> control effects) in humans because of those variations. <a href="/wiki/Pig" title="Pig">Porcine</a> insulin is especially close to the <a href="/wiki/Human" title="Human">human</a> version.</p>
<table id="toc" class="toc">
<tr>
<td>
<div id="toctitle">
<h2>Contents</h2>
</div>
<ul>
<li class="toclevel-1 tocsection-1"><a href="#Gene"><span class="tocnumber">1</span> <span class="toctext">Gene</span></a>
<ul>
<li class="toclevel-2 tocsection-2"><a href="#Alleles"><span class="tocnumber">1.1</span> <span class="toctext">Alleles</span></a></li>
<li class="toclevel-2 tocsection-3"><a href="#Regulation"><span class="tocnumber">1.2</span> <span class="toctext">Regulation</span></a></li>
</ul>
</li>
<li class="toclevel-1 tocsection-4"><a href="#Protein_structure"><span class="tocnumber">2</span> <span class="toctext">Protein structure</span></a></li>
<li class="toclevel-1 tocsection-5"><a href="#Synthesis.2C_physiological_effects.2C_and_degradation"><span class="tocnumber">3</span> <span class="toctext">Synthesis, physiological effects, and degradation</span></a>
<ul>
<li class="toclevel-2 tocsection-6"><a href="#Synthesis"><span class="tocnumber">3.1</span> <span class="toctext">Synthesis</span></a></li>
<li class="toclevel-2 tocsection-7"><a href="#Release"><span class="tocnumber">3.2</span> <span class="toctext">Release</span></a></li>
<li class="toclevel-2 tocsection-8"><a href="#Oscillations"><span class="tocnumber">3.3</span> <span class="toctext">Oscillations</span></a></li>
<li class="toclevel-2 tocsection-9"><a href="#Blood_content"><span class="tocnumber">3.4</span> <span class="toctext">Blood content</span></a></li>
<li class="toclevel-2 tocsection-10"><a href="#Signal_transduction"><span class="tocnumber">3.5</span> <span class="toctext">Signal transduction</span></a></li>
<li class="toclevel-2 tocsection-11"><a href="#Low-frequency_internal_motion"><span class="tocnumber">3.6</span> <span class="toctext">Low-frequency internal motion</span></a></li>
<li class="toclevel-2 tocsection-12"><a href="#Physiological_effects"><span class="tocnumber">3.7</span> <span class="toctext">Physiological effects</span></a></li>
<li class="toclevel-2 tocsection-13"><a href="#Degradation"><span class="tocnumber">3.8</span> <span class="toctext">Degradation</span></a></li>
</ul>
</li>
<li class="toclevel-1 tocsection-14"><a href="#Hypoglycemia"><span class="tocnumber">4</span> <span class="toctext">Hypoglycemia</span></a></li>
<li class="toclevel-1 tocsection-15"><a href="#Diseases_and_syndromes"><span class="tocnumber">5</span> <span class="toctext">Diseases and syndromes</span></a></li>
<li class="toclevel-1 tocsection-16"><a href="#As_a_medication"><span class="tocnumber">6</span> <span class="toctext">As a medication</span></a></li>
<li class="toclevel-1 tocsection-17"><a href="#History"><span class="tocnumber">7</span> <span class="toctext">History</span></a>
<ul>
<li class="toclevel-2 tocsection-18"><a href="#Discovery"><span class="tocnumber">7.1</span> <span class="toctext">Discovery</span></a></li>
<li class="toclevel-2 tocsection-19"><a href="#Extraction_and_purification_in_Canada"><span class="tocnumber">7.2</span> <span class="toctext">Extraction and purification in Canada</span></a></li>
<li class="toclevel-2 tocsection-20"><a href="#Synthesis_2"><span class="tocnumber">7.3</span> <span class="toctext">Synthesis</span></a></li>
<li class="toclevel-2 tocsection-21"><a href="#Nobel_Prizes"><span class="tocnumber">7.4</span> <span class="toctext">Nobel Prizes</span></a></li>
</ul>
</li>
<li class="toclevel-1 tocsection-22"><a href="#See_also"><span class="tocnumber">8</span> <span class="toctext">See also</span></a></li>
<li class="toclevel-1 tocsection-23"><a href="#References"><span class="tocnumber">9</span> <span class="toctext">References</span></a></li>
<li class="toclevel-1 tocsection-24"><a href="#Further_reading"><span class="tocnumber">10</span> <span class="toctext">Further reading</span></a></li>
<li class="toclevel-1 tocsection-25"><a href="#External_links"><span class="tocnumber">11</span> <span class="toctext">External links</span></a></li>
</ul>
</td>
</tr>
</table>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=1" title="Edit section: Gene">edit</a>]</span> <span class="mw-headline" id="Gene">Gene</span></h2>
<p>The <a href="/wiki/Proinsulin" title="Proinsulin">proinsulin</a> precursor of insulin is encoded by the <i>INS</i> <a href="/wiki/Gene" title="Gene">gene</a>.<sup id="cite_ref-entrez_3-0" class="reference"><a href="#cite_note-entrez-3"><span>[</span>4<span>]</span></a></sup><sup id="cite_ref-pmid6243748_4-0" class="reference"><a href="#cite_note-pmid6243748-4"><span>[</span>5<span>]</span></a></sup></p>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=2" title="Edit section: Alleles">edit</a>]</span> <span class="mw-headline" id="Alleles">Alleles</span></h3>
<p>A variety of mutant <a href="/wiki/Allele" title="Allele">alleles</a> with changes in the coding region have been identified. A <a href="/wiki/Conjoined_gene" title="Conjoined gene">read-through gene</a>, INS-IGF2, overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region.<sup id="cite_ref-entrez_3-1" class="reference"><a href="#cite_note-entrez-3"><span>[</span>4<span>]</span></a></sup></p>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=3" title="Edit section: Regulation">edit</a>]</span> <span class="mw-headline" id="Regulation">Regulation</span></h3>
<p>Several <a href="/wiki/Regulatory_sequence" title="Regulatory sequence">regulatory sequences</a> in the <a href="/wiki/Promoter_(biology)" title="Promoter (biology)" class="mw-redirect">promoter</a> region of the human insulin gene bind to <a href="/wiki/Transcription_factor" title="Transcription factor">transcription factors</a>. In general, the <a href="/wiki/A-box" title="A-box" class="mw-redirect">A-boxes</a> bind to <a href="/wiki/Pdx1" title="Pdx1" class="mw-redirect">Pdx1</a> factors, <a href="/wiki/E-box" title="E-box">E-boxes</a> bind to <a href="/wiki/NeuroD" title="NeuroD">NeuroD</a>, C-boxes bind to <a href="/wiki/MafA" title="MafA" class="mw-redirect">MafA</a>, and <a href="/wiki/CAMP_response_element" title="CAMP response element" class="mw-redirect">cAMP response elements</a> to <a href="/wiki/CREB" title="CREB">CREB</a>. There are also <a href="/wiki/Silencer_(genetics)" title="Silencer (genetics)" class="mw-redirect">silencers</a> that inhibit transcription.</p>
<table class="wikitable">
<caption>Regulatory sequences and their transcription factors for the insulin gene.<sup id="cite_ref-pmid11914736_5-0" class="reference"><a href="#cite_note-pmid11914736-5"><span>[</span>6<span>]</span></a></sup></caption>
<tr>
<th><a href="/wiki/Regulatory_sequence" title="Regulatory sequence">Regulatory sequence</a></th>
<th>binding <a href="/wiki/Transcription_factors" title="Transcription factors" class="mw-redirect">transcription factors</a></th>
</tr>
<tr>
<td><a href="/wiki/ILPR" title="ILPR">ILPR</a></td>
<td><a href="/wiki/DBP_(gene)" title="DBP (gene)">Par1</a></td>
</tr>
<tr>
<td><a href="/wiki/A-box_5_of_insulin_gene" title="A-box 5 of insulin gene">A5</a></td>
<td><a href="/wiki/Pdx1" title="Pdx1" class="mw-redirect">Pdx1</a></td>
</tr>
<tr>
<td><a href="/wiki/Negative_regulatory_element" title="Negative regulatory element">negative regulatory element</a> (NRE)<sup id="cite_ref-pmid17150186_6-0" class="reference"><a href="#cite_note-pmid17150186-6"><span>[</span>7<span>]</span></a></sup></td>
<td><a href="/wiki/Glucocorticoid_receptor" title="Glucocorticoid receptor">glucocorticoid receptor</a>, <a href="/wiki/POU2F1" title="POU2F1">Oct1</a></td>
</tr>
<tr>
<td><a href="/wiki/Z-box_of_insulin_gene" title="Z-box of insulin gene">Z</a> (overlapping NRE and C2)</td>
<td><a href="/w/index.php?title=ISF_(transcription_factor)&amp;action=edit&amp;redlink=1" class="new" title="ISF (transcription factor) (page does not exist)">ISF</a></td>
</tr>
<tr>
<td><a href="/wiki/C2_regulatory_sequence" title="C2 regulatory sequence" class="mw-redirect">C2</a></td>
<td><a href="/wiki/Pax4" title="Pax4" class="mw-redirect">Pax4</a>, <a href="/wiki/MafA" title="MafA" class="mw-redirect">MafA</a>(?)</td>
</tr>
<tr>
<td><a href="/wiki/E-box_2_of_insulin_gene" title="E-box 2 of insulin gene">E2</a></td>
<td><a href="/wiki/USF1" title="USF1">USF1</a>/<a href="/wiki/USF2" title="USF2">USF2</a></td>
</tr>
<tr>
<td><a href="/wiki/A-box_3_of_insulin_gene" title="A-box 3 of insulin gene">A3</a></td>
<td><a href="/wiki/Pdx1" title="Pdx1" class="mw-redirect">Pdx1</a></td>
</tr>
<tr>
<td><a href="/wiki/CREB#cAMP_response_element" title="CREB">CREB RE</a></td>
<td>-</td>
</tr>
<tr>
<td><a href="/wiki/CREB#cAMP_response_element" title="CREB">CREB RE</a></td>
<td><a href="/wiki/CREB" title="CREB">CREB</a>, <a href="/wiki/CREM" title="CREM" class="mw-redirect">CREM</a></td>
</tr>
<tr>
<td><a href="/wiki/A-box_2_of_insulin_gene" title="A-box 2 of insulin gene">A2</a></td>
<td>-</td>
</tr>
<tr>
<td><a href="/wiki/CAAT_enhancer_binding" title="CAAT enhancer binding">CAAT enhancer binding</a> (CEB) (partly overlapping A2 and C1)</td>
<td>-</td>
</tr>
<tr>
<td><a href="/wiki/C-box_1_of_insulin_gene" title="C-box 1 of insulin gene">C1</a></td>
<td>-</td>
</tr>
<tr>
<td><a href="/wiki/E-box_1_of_insulin_gene" title="E-box 1 of insulin gene">E1</a></td>
<td><a href="/wiki/E2A" title="E2A" class="mw-redirect">E2A</a>, <a href="/wiki/NeuroD1" title="NeuroD1" class="mw-redirect">NeuroD1</a>, <a href="/wiki/TCF12" title="TCF12">HEB</a></td>
</tr>
<tr>
<td><a href="/w/index.php?title=A-box_1_of_insulin_gene&amp;action=edit&amp;redlink=1" class="new" title="A-box 1 of insulin gene (page does not exist)">A1</a></td>
<td><a href="/wiki/Pdx1" title="Pdx1" class="mw-redirect">Pdx1</a></td>
</tr>
<tr>
<td><a href="/wiki/G-box_1_of_insulin_gene" title="G-box 1 of insulin gene">G1</a></td>
<td>-</td>
</tr>
</table>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=4" title="Edit section: Protein structure">edit</a>]</span> <span class="mw-headline" id="Protein_structure">Protein structure</span></h2>
<div class="rellink boilerplate seealso">See also: <a href="/wiki/Insulin/IGF/Relaxin_family" title="Insulin/IGF/Relaxin family">Insulin/IGF/Relaxin family</a></div>
<p>Within vertebrates, the amino acid sequence of insulin is extremely well-preserved. <a href="/wiki/Cow" title="Cow" class="mw-redirect">Bovine</a> insulin differs from human in only three <a href="/wiki/Amino_acid" title="Amino acid">amino acid</a> residues, and <a href="/wiki/Pig" title="Pig">porcine</a> insulin in one. Even insulin from some species of fish is similar enough to human to be clinically effective in humans. Insulin in some invertebrates is quite similar in sequence to human insulin, and has similar physiological effects. The strong homology seen in the insulin sequence of diverse species suggests that it has been conserved across much of animal evolutionary history. The C-peptide of <a href="/wiki/Proinsulin" title="Proinsulin">proinsulin</a> (discussed later), however, differs much more among species; it is also a hormone, but a secondary one.</p>
<p>The primary structure of bovine insulin was first determined by <a href="/wiki/Frederick_Sanger" title="Frederick Sanger">Frederick Sanger</a> in 1951.<sup id="cite_ref-sanger_7-0" class="reference"><a href="#cite_note-sanger-7"><span>[</span>8<span>]</span></a></sup> After that, this polypeptide was synthesized independently by several groups.<sup id="cite_ref-Katsoyannis_1964_8-0" class="reference"><a href="#cite_note-Katsoyannis_1964-8"><span>[</span>9<span>]</span></a></sup><sup id="cite_ref-pmid5881570_9-0" class="reference"><a href="#cite_note-pmid5881570-9"><span>[</span>10<span>]</span></a></sup><sup id="cite_ref-Marglin_1966_10-0" class="reference"><a href="#cite_note-Marglin_1966-10"><span>[</span>11<span>]</span></a></sup></p>
<p>Insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules), while the active form is the monomer. The hexamer is an inactive form with long-term stability, which serves as a way to keep the highly reactive insulin protected, yet readily available. The hexamer-monomer conversion is one of the central aspects of insulin formulations for injection. The hexamer is far more stable than the monomer, which is desirable for practical reasons; however, the monomer is a much faster-reacting drug because diffusion rate is inversely related to particle size. A fast-reacting drug means insulin injections do not have to precede mealtimes by hours, which in turn gives diabetics more flexibility in their daily schedules.<sup id="cite_ref-pmid16158220_11-0" class="reference"><a href="#cite_note-pmid16158220-11"><span>[</span>12<span>]</span></a></sup> Insulin can aggregate and form <a href="/wiki/Fibrillar" title="Fibrillar" class="mw-redirect">fibrillar</a> interdigitated <a href="/wiki/Beta-sheet" title="Beta-sheet" class="mw-redirect">beta-sheets</a>. This can cause injection <a href="/wiki/Amyloidosis" title="Amyloidosis">amyloidosis</a>, and prevents the storage of insulin for long periods.<sup id="cite_ref-pmid19864624_12-0" class="reference"><a href="#cite_note-pmid19864624-12"><span>[</span>13<span>]</span></a></sup></p>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=5" title="Edit section: Synthesis, physiological effects, and degradation">edit</a>]</span> <span class="mw-headline" id="Synthesis.2C_physiological_effects.2C_and_degradation">Synthesis, physiological effects, and degradation</span></h2>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=6" title="Edit section: Synthesis">edit</a>]</span> <span class="mw-headline" id="Synthesis">Synthesis</span></h3>
<p>Insulin is produced in the <a href="/wiki/Pancreas" title="Pancreas">pancreas</a> and released when any of several stimuli are detected. These stimuli include ingested protein and glucose in the blood produced from digested food. <a href="/wiki/Carbohydrate" title="Carbohydrate">Carbohydrates</a> can be polymers of simple sugars or the simple sugars themselves. If the carbohydrates include glucose, then that glucose will be absorbed into the bloodstream and blood glucose level will begin to rise. In target cells, insulin initiates a <a href="/wiki/Signal_transduction" title="Signal transduction">signal transduction</a>, which has the effect of increasing <a href="/wiki/Glucose" title="Glucose">glucose</a> uptake and storage. Finally, insulin is degraded, terminating the response.</p>
<div class="thumb tright">
<div class="thumbinner" style="width:402px;"><a href="/wiki/File:Insulinpath.png" class="image"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/2/25/Insulinpath.png/400px-Insulinpath.png" width="400" height="566" class="thumbimage" /></a>
<div class="thumbcaption">
<div class="magnify"><a href="/wiki/File:Insulinpath.png" class="internal" title="Enlarge"><img src="//bits.wikimedia.org/skins-1.19/common/images/magnify-clip.png" width="15" height="11" alt="" /></a></div>
Insulin undergoes extensive posttranslational modification along the production pathway. Production and secretion are largely independent; prepared insulin is stored awaiting secretion. Both C-peptide and mature insulin are biologically active. Cell components and proteins in this image are not to scale.</div>
</div>
</div>
<p>In mammals, insulin is synthesized in the pancreas within the <a href="/wiki/Beta_cell" title="Beta cell">β-cells</a> of the <a href="/wiki/Islets_of_Langerhans" title="Islets of Langerhans">islets of Langerhans</a>. One million to three million islets of Langerhans (pancreatic islets) form the <a href="/wiki/Endocrine" title="Endocrine" class="mw-redirect">endocrine</a> part of the pancreas, which is primarily an <a href="/wiki/Exocrine" title="Exocrine" class="mw-redirect">exocrine</a> <a href="/wiki/Gland" title="Gland">gland</a>. The endocrine portion accounts for only 2% of the total mass of the pancreas. Within the islets of Langerhans, beta cells constitute 65–80% of all the cells.</p>
<p>In β-cells, insulin is synthesized from the <a href="/wiki/Proinsulin" title="Proinsulin">proinsulin</a> precursor molecule by the action of proteolytic enzymes, known as <a href="/wiki/Prohormone_convertase" title="Prohormone convertase" class="mw-redirect">prohormone convertases</a> (<a href="/wiki/Proprotein_convertase_1" title="Proprotein convertase 1">PC1</a> and <a href="/wiki/Proprotein_convertase_2" title="Proprotein convertase 2">PC2</a>), as well as the exoprotease <a href="/wiki/Carboxypeptidase_E" title="Carboxypeptidase E">carboxypeptidase E</a>.<sup id="cite_ref-pmid16591494_13-0" class="reference"><a href="#cite_note-pmid16591494-13"><span>[</span>14<span>]</span></a></sup> These modifications of proinsulin remove the center portion of the molecule (i.e., <a href="/wiki/C-peptide" title="C-peptide">C-peptide</a>), from the C- and N- terminal ends of proinsulin. The remaining polypeptides (51 amino acids in total), the B- and A- chains, are bound together by <a href="/wiki/Disulfide_bond" title="Disulfide bond">disulfide bonds</a>. However, the primary sequence of proinsulin goes in the order "B-C-A", since B and A chains were identified on the basis of mass, and the C-peptide was discovered after the others.</p>
<p>The endogenous production of insulin is regulated in several steps along the synthesis pathway:</p>
<ul>
<li>At <a href="/wiki/DNA_transcription" title="DNA transcription" class="mw-redirect">transcription</a> from the <a href="/wiki/Insulin_gene" title="Insulin gene" class="mw-redirect">insulin gene</a></li>
<li>In <a href="/wiki/MRNA" title="MRNA" class="mw-redirect">mRNA</a> stability</li>
<li>At the <a href="/wiki/MRNA_translation" title="MRNA translation" class="mw-redirect">mRNA translation</a></li>
<li>In the <a href="/wiki/Posttranslational_modification" title="Posttranslational modification">posttranslational modifications</a></li>
</ul>
<p>Insulin and its related proteins have been shown to be produced inside the brain, and reduced levels of these proteins are linked to Alzheimer's disease.<sup id="cite_ref-urlResearchers_discover_link_between_insulin_and_Alzheimers_14-0" class="reference"><a href="#cite_note-urlResearchers_discover_link_between_insulin_and_Alzheimers-14"><span>[</span>15<span>]</span></a></sup><sup id="cite_ref-pmid15750214_15-0" class="reference"><a href="#cite_note-pmid15750214-15"><span>[</span>16<span>]</span></a></sup><sup id="cite_ref-pmid15750215_16-0" class="reference"><a href="#cite_note-pmid15750215-16"><span>[</span>17<span>]</span></a></sup></p>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=7" title="Edit section: Release">edit</a>]</span> <span class="mw-headline" id="Release">Release</span></h3>
<div class="rellink boilerplate seealso">See also: <a href="/wiki/Blood_glucose_regulation" title="Blood glucose regulation" class="mw-redirect">Blood glucose regulation</a></div>
<p>Beta cells in the <a href="/wiki/Islets_of_Langerhans" title="Islets of Langerhans">islets of Langerhans</a> release insulin in two phases. The first phase release is rapidly triggered in response to increased blood glucose levels. The second phase is a sustained, slow release of newly formed vesicles triggered independently of sugar. The description of first phase release is as follows:</p>
<ul>
<li>Glucose enters the β-cells through the <a href="/wiki/Glucose_transporter" title="Glucose transporter">glucose transporter</a> <a href="/wiki/GLUT2" title="GLUT2">GLUT2</a></li>
<li>Glucose goes into <a href="/wiki/Glycolysis" title="Glycolysis">glycolysis</a> and the respiratory cycle, where multiple high-energy <a href="/wiki/Adenosine_triphosphate" title="Adenosine triphosphate">ATP</a> molecules are produced by oxidation</li>
<li>Increased intracellular ATP:ADP ratio closes the ATP-dependent SUR1/<a href="/wiki/Kir6.2" title="Kir6.2">Kir6.2</a> <a href="/wiki/Potassium_channel" title="Potassium channel">potassium channel</a> (see <a href="/wiki/Sulfonylurea_receptor" title="Sulfonylurea receptor">sulfonylurea receptor</a>). The cell membrane potential depolarizes.</li>
<li>On <a href="/wiki/Depolarization" title="Depolarization">depolarization</a>, voltage-controlled <a href="/wiki/Calcium_channels" title="Calcium channels" class="mw-redirect">calcium channels</a> (Ca<sup>2+</sup>) open and calcium flows into the cells</li>
<li>An increased calcium level causes activation of <a href="/wiki/Phospholipase" title="Phospholipase">phospholipase C</a>, which cleaves the membrane phospholipid <a href="/wiki/Phosphatidyl_inositol_4,5-bisphosphate" title="Phosphatidyl inositol 4,5-bisphosphate" class="mw-redirect">phosphatidyl inositol 4,5-bisphosphate</a> into <a href="/wiki/Inositol_1,4,5-triphosphate" title="Inositol 1,4,5-triphosphate" class="mw-redirect">inositol 1,4,5-triphosphate</a> and <a href="/wiki/Diglyceride" title="Diglyceride">diacylglycerol</a>.</li>
<li>Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of <a href="/wiki/Endoplasmic_reticulum" title="Endoplasmic reticulum">endoplasmic reticulum</a> (ER). This allows the release of Ca<sup>2+</sup> from the ER via IP3-gated channels, and further raises the cell concentration of calcium.</li>
<li>Significantly increased amounts of calcium in the cells causes release of previously synthesized insulin, which has been stored in <a href="/wiki/Secretion" title="Secretion">secretory</a> <a href="/wiki/Vesicle_(biology)" title="Vesicle (biology)" class="mw-redirect">vesicles</a></li>
</ul>
<p>This is the primary mechanism for release of insulin. Other substances known to stimulate insulin release include the amino acids arginine and leucine, parasympathetic release of <a href="/wiki/Acetylcholine" title="Acetylcholine">acetylcholine</a> (via phospholipase C), <a href="/wiki/Sulfonylurea" title="Sulfonylurea">sulfonylurea</a>, <a href="/wiki/Cholecystokinin" title="Cholecystokinin">cholecystokinin</a> (CCK, via phospholipase C)<sup id="cite_ref-CawstonMiller2010_17-0" class="reference"><a href="#cite_note-CawstonMiller2010-17"><span>[</span>18<span>]</span></a></sup>, and the gastrointestinally-derived <a href="/wiki/Incretins" title="Incretins" class="mw-redirect">incretins</a> <a href="/wiki/Glucagon-like_peptide-1" title="Glucagon-like peptide-1">glucagon-like peptide-1</a> (GLP-1) and <a href="/wiki/Glucose-dependent_insulinotropic_peptide" title="Glucose-dependent insulinotropic peptide" class="mw-redirect">glucose-dependent insulinotropic peptide</a> (GIP).</p>
<p>The <a href="/wiki/Sympathetic_nervous_system" title="Sympathetic nervous system">sympathetic nervous system</a> (via α<sub>2</sub>-adrenergic stimulation as demonstrated by the agonists <a href="/wiki/Clonidine" title="Clonidine">clonidine</a> or <a href="/wiki/Methyldopa" title="Methyldopa">methyldopa</a>) inhibit the release of insulin. However, it is worth noting that <a href="/wiki/Epinephrine" title="Epinephrine">epinephrine</a> activates β<sub>2</sub>-receptors on the β-cells in the pancreatic islets to promote insulin release.<sup id="cite_ref-18" class="reference"><a href="#cite_note-18"><span>[</span>19<span>]</span></a></sup> This is important, since muscle cannot benefit from the raised blood sugar resulting from adrenergic stimulation (increased gluconeogenesis and glycogenolysis from the low blood insulin: glucagon state) unless insulin is present to allow for GLUT-4 translocation in the tissue. Therefore, beginning with direct innervation, <a href="/wiki/Norepinephrine" title="Norepinephrine">norepinephrine</a> inhibits insulin release via α<sub>2</sub>-receptors, then subsequently, circulating <a href="/wiki/Epinephrine" title="Epinephrine">epinephrine</a> from the <a href="/wiki/Adrenal_medulla" title="Adrenal medulla">adrenal medulla</a> will stimulate β<sub>2</sub>-receptors, thereby promoting insulin release.</p>
<p>When the glucose level comes down to the usual physiologic value, insulin release from the β-cells slows or stops. If blood glucose levels drop lower than this, especially to dangerously low levels, release of hyperglycemic hormones (most prominently <a href="/wiki/Glucagon" title="Glucagon">glucagon</a> from islet of Langerhans alpha cells) forces release of glucose into the blood from cellular stores, primarily liver cell stores of glycogen. By increasing blood glucose, the hyperglycemic hormones prevent or correct life-threatening hypoglycemia. Release of insulin is strongly inhibited by the <a href="/wiki/Stress_hormone" title="Stress hormone">stress hormone</a> <a href="/wiki/Norepinephrine" title="Norepinephrine">norepinephrine</a> (noradrenaline), which leads to increased blood glucose levels during stress.</p>
<p>Evidence of impaired first-phase insulin release can be seen in the <a href="/wiki/Glucose_tolerance_test" title="Glucose tolerance test">glucose tolerance test</a>, demonstrated by a substantially elevated blood glucose level at 30 minutes, a marked drop by 60 minutes, and a steady climb back to baseline levels over the following hourly time points.</p>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=8" title="Edit section: Oscillations">edit</a>]</span> <span class="mw-headline" id="Oscillations">Oscillations</span></h3>
<div class="rellink relarticle mainarticle">Main article: <a href="/wiki/Insulin_oscillations" title="Insulin oscillations" class="mw-redirect">Insulin oscillations</a></div>
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<div class="thumbinner" style="width:252px;"><a href="/wiki/File:Pancreas_insulin_oscillations.svg" class="image"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/7/7e/Pancreas_insulin_oscillations.svg/250px-Pancreas_insulin_oscillations.svg.png" width="250" height="77" class="thumbimage" /></a>
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Insulin release from pancreas oscillates with a period of 3–6&#160;minutes.<sup id="cite_ref-hellman_19-0" class="reference"><a href="#cite_note-hellman-19"><span>[</span>20<span>]</span></a></sup></div>
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<p>Even during digestion, in general, one or two hours following a meal, insulin release from the pancreas is not continuous, but <a href="/wiki/Oscillates" title="Oscillates" class="mw-redirect">oscillates</a> with a period of 3–6&#160;minutes, changing from generating a blood insulin concentration more than about 800 <a href="/wiki/Pico-" title="Pico-">p</a><a href="/wiki/Unit_mole" title="Unit mole" class="mw-redirect">mol</a>/l to less than 100 pmol/l.<sup id="cite_ref-hellman_19-1" class="reference"><a href="#cite_note-hellman-19"><span>[</span>20<span>]</span></a></sup> This is thought to avoid <a href="/wiki/Receptor_downregulation" title="Receptor downregulation" class="mw-redirect">downregulation</a> of <a href="/wiki/Insulin_receptor" title="Insulin receptor">insulin receptors</a> in target cells, and to assist the liver in extracting insulin from the blood.<sup id="cite_ref-hellman_19-2" class="reference"><a href="#cite_note-hellman-19"><span>[</span>20<span>]</span></a></sup> This oscillation is important to consider when administering insulin-stimulating medication, since it is the oscillating blood concentration of insulin release, which should, ideally, be achieved, not a constant high concentration.<sup id="cite_ref-hellman_19-3" class="reference"><a href="#cite_note-hellman-19"><span>[</span>20<span>]</span></a></sup> This may be achieved by delivering insulin rhythmically to the <a href="/wiki/Portal_vein" title="Portal vein" class="mw-redirect">portal vein</a> or by <a href="/wiki/Islet_cell_transplantation" title="Islet cell transplantation">islet cell transplantation</a> to the liver.<sup id="cite_ref-hellman_19-4" class="reference"><a href="#cite_note-hellman-19"><span>[</span>20<span>]</span></a></sup> Future insulin pumps hope to address this characteristic. (See also <a href="/wiki/Pulsatile_Insulin" title="Pulsatile Insulin" class="mw-redirect">Pulsatile Insulin</a>.)</p>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=9" title="Edit section: Blood content">edit</a>]</span> <span class="mw-headline" id="Blood_content">Blood content</span></h3>
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The idealized diagram shows the fluctuation of <a href="/wiki/Blood_sugar" title="Blood sugar">blood sugar</a> (red) and the sugar-lowering hormone <b>insulin</b> (blue) in humans during the course of a day containing three meals. In addition, the effect of a <a href="/wiki/Sucrose" title="Sucrose">sugar</a>-rich versus a <a href="/wiki/Starch" title="Starch">starch</a>-rich meal is highlighted.</div>
</div>
</div>
<p>The blood content of insulin can be measured in <a href="/wiki/International_unit" title="International unit">international units</a>, such as µIU/mL or in <a href="/wiki/Molar_concentration" title="Molar concentration">molar concentration</a>, such as pmol/L, where 1 µIU/mL equals 6.945 pmol/L.<sup id="cite_ref-20" class="reference"><a href="#cite_note-20"><span>[</span>21<span>]</span></a></sup> A typical blood level between meals is 8–11 μIU/mL (57–79 pmol/L).<sup id="cite_ref-21" class="reference"><a href="#cite_note-21"><span>[</span>22<span>]</span></a></sup></p>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=10" title="Edit section: Signal transduction">edit</a>]</span> <span class="mw-headline" id="Signal_transduction">Signal transduction</span></h3>
<p>Special transporter proteins in <a href="/wiki/Cell_membrane" title="Cell membrane">cell membranes</a> allow glucose from the blood to enter a cell. These transporters are, indirectly, under blood insulin's control in certain body cell types (e.g., muscle cells). Low levels of circulating insulin, or its absence, will prevent glucose from entering those cells (e.g., in type 1 diabetes). More commonly, however, there is a decrease in the sensitivity of cells to insulin (e.g., the reduced insulin sensitivity characteristic of type 2 diabetes), resulting in decreased glucose absorption. In either case, there is 'cell starvation' and weight loss, sometimes extreme. In a few cases, there is a defect in the release of insulin from the pancreas. Either way, the effect is the same: elevated blood glucose levels.</p>
<p>Activation of <a href="/wiki/Insulin_receptor" title="Insulin receptor">insulin receptors</a> leads to internal cellular mechanisms that directly affect glucose uptake by regulating the number and operation of protein molecules in the cell membrane that transport glucose into the cell. The genes that specify the proteins that make up the insulin receptor in cell membranes have been identified, and the structures of the interior, transmembrane section, and the extra-membrane section of receptor have been solved.</p>
<p>Two types of tissues are most strongly influenced by insulin, as far as the stimulation of glucose uptake is concerned: muscle cells (<a href="/wiki/Myocyte" title="Myocyte">myocytes</a>) and fat cells (<a href="/wiki/Adipocyte" title="Adipocyte">adipocytes</a>). The former are important because of their central role in movement, breathing, circulation, etc., and the latter because they accumulate excess <a href="/wiki/Food_energy" title="Food energy">food energy</a> against future needs. Together, they account for about two-thirds of all cells in a typical human body.</p>
<p>Insulin binds to the extracellular portion of the alpha subunits of the insulin receptor. This, in turn, causes a conformational change in the insulin receptor that activates the kinase domain residing on the intracellular portion of the beta subunits. The activated kinase domain autophosphorylates tyrosine residues on the <a href="/wiki/C-terminus" title="C-terminus">C-terminus</a> of the receptor as well as tyrosine residues in the <a href="/wiki/IRS-1" title="IRS-1" class="mw-redirect">IRS-1</a> protein.</p>
<ol>
<li>phosphorylated IRS-1, in turn, binds to and activates phosphoinositol 3 kinase (<a href="/wiki/Phosphoinositide_3-kinase" title="Phosphoinositide 3-kinase">PI3K</a>)</li>
<li>PI3K catalyzes the reaction <a href="/wiki/Phosphatidylinositol_4,5-bisphosphate" title="Phosphatidylinositol 4,5-bisphosphate">PIP2</a> + <a href="/wiki/Adenosine_triphosphate" title="Adenosine triphosphate">ATP</a> → <a href="/wiki/Phosphatidylinositol_(3,4,5)-trisphosphate" title="Phosphatidylinositol (3,4,5)-trisphosphate">PIP3</a></li>
<li>PIP3 activates protein kinase B (<a href="/wiki/AKT" title="AKT">PKB</a>)</li>
<li>PKB phosphorylates glycogen synthase kinase (<a href="/wiki/GSK-3" title="GSK-3">GSK</a>) and thereby inactivates GSK<sup id="cite_ref-22" class="reference"><a href="#cite_note-22"><span>[</span>23<span>]</span></a></sup></li>
<li>GSK can no longer phosphorylate glycogen synthase (<a href="/wiki/Glycogen_synthase" title="Glycogen synthase">GS</a>)</li>
<li>unphosphorylated GS makes more <a href="/wiki/Glycogen" title="Glycogen">glycogen</a></li>
<li>PKB also facilitates vesicle fusion, resulting in an increase in GLUT4 transporters in the plasma membrane<sup id="cite_ref-23" class="reference"><a href="#cite_note-23"><span>[</span>24<span>]</span></a></sup></li>
</ol>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=11" title="Edit section: Low-frequency internal motion">edit</a>]</span> <span class="mw-headline" id="Low-frequency_internal_motion">Low-frequency internal motion</span></h3>
<div class="rellink boilerplate seealso">See also: <a href="/wiki/Low-frequency_collective_motion_in_proteins_and_DNA" title="Low-frequency collective motion in proteins and DNA">Low-frequency collective motion in proteins and DNA</a></div>
<p>According to the study of Raman spectra, a low-frequency wave number of 22&#160;cm<sup>−1</sup> has been observed for insulin molecules.<sup id="cite_ref-pmid7115900_24-0" class="reference"><a href="#cite_note-pmid7115900-24"><span>[</span>25<span>]</span></a></sup> Subsequently, it was identified as the accordion-like vibration of the helix (B9-B19) in the B-chain of insulin.<sup id="cite_ref-pmid6362659_25-0" class="reference"><a href="#cite_note-pmid6362659-25"><span>[</span>26<span>]</span></a></sup><sup id="cite_ref-pmid3046672_26-0" class="reference"><a href="#cite_note-pmid3046672-26"><span>[</span>27<span>]</span></a></sup></p>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=12" title="Edit section: Physiological effects">edit</a>]</span> <span class="mw-headline" id="Physiological_effects">Physiological effects</span></h3>
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<b>Effect of insulin on glucose uptake and metabolism.</b> Insulin binds to its receptor (1), which starts many protein activation cascades (2). These include translocation of Glut-4 transporter to the <a href="/wiki/Plasma_membrane" title="Plasma membrane" class="mw-redirect">plasma membrane</a> and influx of glucose (3), <a href="/wiki/Glycogen" title="Glycogen">glycogen</a> synthesis (4), <a href="/wiki/Glycolysis" title="Glycolysis">glycolysis</a> (5) and <a href="/wiki/Fatty_acid" title="Fatty acid">fatty acid</a> synthesis (6).</div>
</div>
</div>
<p>The actions of insulin on the global human metabolism level include:</p>
<ul>
<li>Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about two-thirds of body cells)</li>
<li>Increase of <a href="/wiki/DNA_replication" title="DNA replication">DNA replication</a> and <a href="/wiki/Protein_synthesis" title="Protein synthesis" class="mw-redirect">protein synthesis</a> via control of amino acid uptake</li>
<li>Modification of the activity of numerous <a href="/wiki/Enzymes" title="Enzymes" class="mw-redirect">enzymes</a></li>
</ul>
<p>The actions of insulin (indirect and direct) on cells include:</p>
<ul>
<li>Increased glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin, which is directly useful in reducing high blood glucose levels as in diabetes.</li>
<li>Increased lipid synthesis – insulin forces fat cells to take in blood lipids, which are converted to <a href="/wiki/Triglycerides" title="Triglycerides" class="mw-redirect">triglycerides</a>; lack of insulin causes the reverse.</li>
<li>Increased <a href="/wiki/Esterification" title="Esterification" class="mw-redirect">esterification</a> of fatty acids – forces adipose tissue to make fats (i.e., triglycerides) from fatty acid esters; lack of insulin causes the reverse.</li>
<li>Decreased <a href="/wiki/Proteolysis" title="Proteolysis">proteolysis</a> – decreasing the breakdown of protein</li>
<li>Decreased <a href="/wiki/Lipolysis" title="Lipolysis">lipolysis</a> – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse.</li>
<li>Decreased <a href="/wiki/Gluconeogenesis" title="Gluconeogenesis">gluconeogenesis</a> – decreases production of glucose from nonsugar substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); lack of insulin causes glucose production from assorted substrates in the liver and elsewhere.</li>
<li>Decreased <a href="/wiki/Autophagy_(cellular)" title="Autophagy (cellular)" class="mw-redirect">autophagy</a> - decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely.<sup id="cite_ref-pmid17934054_27-0" class="reference"><a href="#cite_note-pmid17934054-27"><span>[</span>28<span>]</span></a></sup></li>
<li>Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption.</li>
<li>Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood. This possible occurs via insulin-induced translocation of the <a href="/wiki/Na%2B/K%2B-ATPase" title="Na+/K+-ATPase">Na+/K+-ATPase</a> to the surface of skeletal muscle cells.<sup id="cite_ref-28" class="reference"><a href="#cite_note-28"><span>[</span>29<span>]</span></a></sup><sup id="cite_ref-29" class="reference"><a href="#cite_note-29"><span>[</span>30<span>]</span></a></sup></li>
<li>Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in microarteries; lack of insulin reduces flow by allowing these muscles to contract.</li>
<li>Increase in the secretion of hydrochloric acid by parietal cells in the stomach</li>
<li>Decreased renal sodium excretion.<sup id="cite_ref-30" class="reference"><a href="#cite_note-30"><span>[</span>31<span>]</span></a></sup></li>
</ul>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=13" title="Edit section: Degradation">edit</a>]</span> <span class="mw-headline" id="Degradation">Degradation</span></h3>
<p>Once an insulin molecule has docked onto the receptor and effected its action, it may be released back into the extracellular environment, or it may be degraded by the cell. The two primary sites for insulin clearance are the liver and the kidney. The liver clears most insulin during first-pass transit, whereas the kidney clears most of the insulin in systemic circulation. Degradation normally involves <a href="/wiki/Endocytosis" title="Endocytosis">endocytosis</a> of the insulin-receptor complex, followed by the action of <a href="/wiki/Insulin-degrading_enzyme" title="Insulin-degrading enzyme">insulin-degrading enzyme</a>. An insulin molecule produced endogenously by the pancreatic beta cells is estimated to be degraded within about one hour after its initial release into circulation (insulin <a href="/wiki/Biological_half-life" title="Biological half-life">half-life</a> ~ 4–6&#160;minutes).<sup id="cite_ref-31" class="reference"><a href="#cite_note-31"><span>[</span>32<span>]</span></a></sup><sup id="cite_ref-32" class="reference"><a href="#cite_note-32"><span>[</span>33<span>]</span></a></sup></p>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=14" title="Edit section: Hypoglycemia">edit</a>]</span> <span class="mw-headline" id="Hypoglycemia">Hypoglycemia</span></h2>
<div class="rellink relarticle mainarticle">Main article: <a href="/wiki/Hypoglycemia" title="Hypoglycemia">Hypoglycemia</a></div>
<p>Although other cells can use other fuels (most prominently fatty acids), <a href="/wiki/Neurons" title="Neurons" class="mw-redirect">neurons</a> depend on glucose as a source of energy in the nonstarving human. They do not require insulin to absorb glucose, unlike muscle and adipose tissue, and they have very small internal stores of glycogen. Glycogen stored in liver cells (unlike glycogen stored in muscle cells) can be converted to glucose, and released into the blood, when glucose from digestion is low or absent, and the <a href="/wiki/Glycerol" title="Glycerol">glycerol</a> backbone in triglycerides can also be used to produce blood glucose.</p>
<p>Sufficient lack of glucose and scarcity of these sources of glucose can dramatically make itself manifest in the impaired functioning of the <a href="/wiki/Central_nervous_system" title="Central nervous system">central nervous system</a>: dizziness, speech problems, and even loss of consciousness. Low glucose is known as <a href="/wiki/Hypoglycemia" title="Hypoglycemia">hypoglycemia</a> or, in cases producing unconsciousness, "hypoglycemic coma" (sometimes termed "insulin shock" from the most common causative agent). Endogenous causes of insulin excess (such as an <a href="/wiki/Insulinoma" title="Insulinoma">insulinoma</a>) are very rare, and the overwhelming majority of insulin excess-induced hypoglycemia cases are <a href="/wiki/Iatrogenesis" title="Iatrogenesis">iatrogenic</a> and usually accidental. A few cases of murder, attempted murder, or suicide using insulin overdoses have been reported, but most insulin shocks appear to be due to errors in dosage of insulin (e.g., 20 units instead of 2) or other unanticipated factors (did not eat as much as anticipated, or exercised more than expected, or unpredicted kinetics of the subcutaneously injected insulin itself).</p>
<p>Possible causes of hypoglycemia include:</p>
<ul>
<li>External insulin (usually injected subcutaneously)</li>
<li>Oral hypoglycemic agents (e.g., any of the sulfonylureas, or similar drugs, which increase insulin release from β-cells in response to a particular blood glucose level)</li>
<li>Ingestion of low-carbohydrate sugar substitutes in people without diabetes or with type 2 diabetes. Animal studies show these can trigger insulin release, albeit in much smaller quantities than sugar, according to a report in <i>Discover</i> magazine, August 2004, p 18. (This can never be a cause of hypoglycemia in patients with type 1 diabetes, since there is no endogenous insulin production to stimulate.)</li>
</ul>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=15" title="Edit section: Diseases and syndromes">edit</a>]</span> <span class="mw-headline" id="Diseases_and_syndromes">Diseases and syndromes</span></h2>
<p>There are several conditions in which insulin disturbance is pathologic:</p>
<ul>
<li><a href="/wiki/Diabetes_mellitus" title="Diabetes mellitus">Diabetes mellitus</a> – general term referring to all states characterized by hyperglycemia
<ul>
<li><a href="/wiki/Diabetes_mellitus_type_1" title="Diabetes mellitus type 1">Type 1</a> – autoimmune-mediated destruction of insulin-producing β-cells in the pancreas, resulting in absolute insulin deficiency</li>
<li><a href="/wiki/Diabetes_mellitus_type_2" title="Diabetes mellitus type 2">Type 2</a> – multifactoral syndrome with combined influence of genetic susceptibility and influence of environmental factors, the best known being <a href="/wiki/Obesity" title="Obesity">obesity</a>, age, and physical inactivity, resulting in <a href="/wiki/Insulin_resistance" title="Insulin resistance">insulin resistance</a> in cells requiring insulin for glucose absorption. This form of diabetes is strongly inherited.</li>
<li>Other types of impaired glucose tolerance (see the <a href="/wiki/Diabetes" title="Diabetes" class="mw-redirect">Diabetes</a>)</li>
</ul>
</li>
<li><a href="/wiki/Insulinoma" title="Insulinoma">Insulinoma</a> - a tumor of pancreatic β-cells producing excess insulin or <a href="/wiki/Reactive_hypoglycemia" title="Reactive hypoglycemia">reactive hypoglycemia</a>.</li>
<li><a href="/wiki/Metabolic_syndrome" title="Metabolic syndrome">Metabolic syndrome</a> – a poorly understood condition first called Syndrome X by <a href="/wiki/Gerald_Reaven" title="Gerald Reaven">Gerald Reaven</a>, Reaven's Syndrome after Reaven, CHAOS in Australia (from the signs that seem to travel together). It is currently not clear whether these signs have a single, treatable cause, or are the result of body changes leading to type 2 diabetes. It is characterized by elevated blood pressure, dyslipidemia (disturbances in blood cholesterol forms and other blood lipids), and increased waist circumference (at least in populations in much of the developed world). The basic underlying cause may be the insulin resistance that precedes 2 diabetes, which is a diminished capacity for <a href="/wiki/Insulin#Physiological_effects" title="Insulin">insulin response</a> in some tissues (e.g., muscle, fat). It is common that morbidities, such as essential <a href="/wiki/Hypertension" title="Hypertension">hypertension</a>, <a href="/wiki/Obesity" title="Obesity">obesity</a>, type 2 diabetes, and <a href="/wiki/Cardiovascular_disease" title="Cardiovascular disease">cardiovascular disease</a> (CVD) develop.</li>
<li><a href="/wiki/Polycystic_ovary_syndrome" title="Polycystic ovary syndrome">Polycystic ovary syndrome</a> – a complex syndrome in women in the reproductive years where <a href="/wiki/Anovulation" title="Anovulation">anovulation</a> and <a href="/wiki/Androgen" title="Androgen">androgen</a> excess are commonly displayed as <a href="/wiki/Hirsutism" title="Hirsutism">hirsutism</a>. In many cases of PCOS, insulin resistance is present.</li>
</ul>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=16" title="Edit section: As a medication">edit</a>]</span> <span class="mw-headline" id="As_a_medication">As a medication</span></h2>
<div class="rellink relarticle mainarticle">Main article: <a href="/wiki/Insulin_therapy" title="Insulin therapy">Insulin therapy</a></div>
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Insulin vial</div>
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<p>Biosynthetic "human" insulin is now manufactured for widespread clinical use using <a href="/wiki/Recombinant_DNA#Synthetic_insulin_production_using_recombinant_DNA" title="Recombinant DNA">recombinant DNA</a> technology. More recently, researchers have succeeded in introducing the gene for human insulin into plants and in producing insulin in them, to be specific <a href="/wiki/Safflower" title="Safflower">safflower</a>.<sup id="cite_ref-33" class="reference"><a href="#cite_note-33"><span>[</span>34<span>]</span></a></sup><sup id="cite_ref-34" class="reference"><a href="#cite_note-34"><span>[</span>35<span>]</span></a></sup> This technique is anticipated to reduce production costs.</p>
<p>Several of these slightly modified versions of human insulin, while having a clinical effect on blood glucose levels as though they were exact copies, have been designed to have somewhat different absorption or duration of action characteristics. They are usually referred to as "insulin analogues". For instance, the first one available, insulin lispro, does not exhibit a delayed absorption effect found in regular insulin, and begins to have an effect in as little as 15&#160;minutes. Other rapid-acting analogues are <a href="/wiki/NovoRapid" title="NovoRapid" class="mw-redirect">NovoRapid</a> and <a href="/wiki/Apidra" title="Apidra" class="mw-redirect">Apidra</a>, with similar profiles. All are rapidly absorbed due to a mutation in the sequence that prevents the insulin analogue from forming dimers and hexamers. Instead, the insulin molecule is a monomer, which is more rapidly absorbed. Using it, therefore, does not require the planning required for other insulins that begin to take effect much later (up to many hours) after administration. Another type is extended-release insulin; the first of these was <a href="/wiki/Lantus" title="Lantus" class="mw-redirect">Lantus</a> (insulin glargine). These have a steady effect for the entire time they are active, without the peak and drop of effect in other insulins; typically, they continue to have an insulin effect for an extended period from 18 to 24&#160;hours. Likewise, another protracted insulin analogue (<a href="/wiki/Levemir" title="Levemir" class="mw-redirect">Levemir</a>) is based on a fatty acid acylation approach. A myristyric acid molecule is attached to this analogue, which in turn associates the insulin molecule to the abundant serum albumin, which in turn extends the effect and reduces the risk of hypoglycemia. Both protracted analogues need to be taken only once-daily, and are very much used in the type 1 diabetes market as the basal insulin. A combination of a rapid acting and a protracted insulin is also available for the patients, making it more likely for them to achieve an insulin profile that mimics that of the body´s own insulin release.</p>
<p>Unlike many medicines, insulin currently cannot be taken orally because, like nearly all other proteins introduced into the <a href="/wiki/Gastrointestinal_tract" title="Gastrointestinal tract" class="mw-redirect">gastrointestinal tract</a>, it is reduced to fragments (even single amino acid components), whereupon all activity is lost. There has been some research into ways to protect insulin from the digestive tract, so that it can be administered orally or sublingually. While experimental, several companies now have various formulations in human clinical trials.<sup id="cite_ref-35" class="reference"><a href="#cite_note-35"><span>[</span>36<span>]</span></a></sup><sup class="Template-Fact" style="white-space:nowrap;">[<i><a href="/wiki/Wikipedia:Citation_needed" title="Wikipedia:Citation needed"><span title="This claim needs references to reliable sources from January 2010">citation needed</span></a></i>]</sup></p>
<p>Insulin is usually taken as <a href="/wiki/Subcutaneous" title="Subcutaneous" class="mw-redirect">subcutaneous</a> <a href="/wiki/Injection_(medicine)" title="Injection (medicine)">injections</a> by single-use <a href="/wiki/Syringe" title="Syringe">syringes</a> with <a href="/wiki/Hypodermic_needle" title="Hypodermic needle">needles</a>, via an <a href="/wiki/Insulin_pump" title="Insulin pump">insulin pump</a>, or by repeated-use <a href="/wiki/Insulin_pen" title="Insulin pen">insulin pens</a> with needles.</p>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=17" title="Edit section: History">edit</a>]</span> <span class="mw-headline" id="History">History</span></h2>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=18" title="Edit section: Discovery">edit</a>]</span> <span class="mw-headline" id="Discovery">Discovery</span></h3>
<p>In 1869 <a href="/wiki/Paul_Langerhans" title="Paul Langerhans">Paul Langerhans</a>, a medical student in <a href="/wiki/Berlin" title="Berlin">Berlin</a>, was studying the structure of the <a href="/wiki/Pancreas" title="Pancreas">pancreas</a> under a <a href="/wiki/Microscope" title="Microscope">microscope</a> when he identified some previously unnoticed tissue clumps scattered throughout the bulk of the pancreas. The function of the "little heaps of cells", later <a href="/wiki/Eponym" title="Eponym">known as</a> the <i><a href="/wiki/Islets_of_Langerhans" title="Islets of Langerhans">islets of Langerhans</a></i>, was unknown, but <a href="/wiki/Edouard_Laguesse" title="Edouard Laguesse">Edouard Laguesse</a> later suggested they might produce secretions that play a regulatory role in digestion. Paul Langerhans' son, Archibald, also helped to understand this regulatory role. The term "insulin" origins from <i>insula</i>, the Latin word for islet/island.</p>
<p>In 1889, the <a href="/wiki/Poles_in_Germany" title="Poles in Germany">Polish-German</a> physician <a href="/wiki/Oscar_Minkowski" title="Oscar Minkowski" class="mw-redirect">Oscar Minkowski</a>, in collaboration with <a href="/wiki/Joseph_von_Mering" title="Joseph von Mering">Joseph von Mering</a>, removed the pancreas from a healthy dog to test its assumed role in digestion. Several days after the dog's pancreas was removed, Minkowski's animal keeper noticed a swarm of flies feeding on the dog's urine. On testing the urine, they found there was sugar in the dog's urine, establishing for the first time a relationship between the pancreas and diabetes. In 1901, another major step was taken by <a href="/w/index.php?title=Eugene_Opie&amp;action=edit&amp;redlink=1" class="new" title="Eugene Opie (page does not exist)">Eugene Opie</a>, when he clearly established the link between the islets of Langerhans and diabetes: "Diabetes mellitus . . . is caused by destruction of the islets of Langerhans and occurs only when these bodies are in part or wholly destroyed." Before his work, the link between the pancreas and diabetes was clear, but not the specific role of the islets.</p>
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<b>The structure of insulin.</b> The left side is a space-filling model of the insulin monomer, believed to be biologically active. <a href="/wiki/Carbon" title="Carbon">Carbon</a> is green, <a href="/wiki/Hydrogen" title="Hydrogen">hydrogen</a> white, <a href="/wiki/Oxygen" title="Oxygen">oxygen</a> red, and <a href="/wiki/Nitrogen" title="Nitrogen">nitrogen</a> blue. On the right side is a <a href="/wiki/Ribbon_diagram" title="Ribbon diagram">ribbon diagram</a> of the insulin hexamer, believed to be the stored form. A monomer unit is highlighted with the A chain in blue and the B chain in cyan. Yellow denotes disulfide bonds, and magenta spheres are zinc ions.</div>
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<p>Over the next two decades, several attempts were made to isolate whatever it was the islets produced as a potential treatment. In 1906, <a href="/wiki/George_Ludwig_Zuelzer" title="George Ludwig Zuelzer">George Ludwig Zuelzer</a> was partially successful treating dogs with pancreatic extract, but was unable to continue his work. Between 1911 and 1912, <a href="/w/index.php?title=E.L._Scott&amp;action=edit&amp;redlink=1" class="new" title="E.L. Scott (page does not exist)">E.L. Scott</a> at the <a href="/wiki/University_of_Chicago" title="University of Chicago">University of Chicago</a> used aqueous pancreatic extracts, and noted "a slight diminution of glycosuria", but was unable to convince his director of his work's value; it was shut down. <a href="/wiki/Israel_Kleiner_(biochemist)" title="Israel Kleiner (biochemist)">Israel Kleiner</a> demonstrated similar effects at <a href="/wiki/Rockefeller_University" title="Rockefeller University">Rockefeller University</a> in 1915, but his work was interrupted by <a href="/wiki/World_War_I" title="World War I">World War I</a>, and he did not return to it.<sup id="cite_ref-J._Nutrition_92_36-0" class="reference"><a href="#cite_note-J._Nutrition_92-36"><span>[</span>37<span>]</span></a></sup></p>
<p><a href="/wiki/Nicolae_Paulescu" title="Nicolae Paulescu">Nicolae Paulescu</a>, a <a href="/wiki/Romanians" title="Romanians">Romanian</a> professor of physiology at the <a href="/wiki/Carol_Davila_University_of_Medicine_and_Pharmacy" title="Carol Davila University of Medicine and Pharmacy">University of Medicine and Pharmacy in Bucharest</a>, developed an <a href="/wiki/Aqueous" title="Aqueous" class="mw-redirect">aqueous</a> <a href="/wiki/Pancreas" title="Pancreas">pancreatic</a> extract which, when injected into a <a href="/wiki/Diabetes" title="Diabetes" class="mw-redirect">diabetic</a> dog, proved to have a normalizing effect on <a href="/wiki/Blood_sugar" title="Blood sugar">blood sugar</a> levels. He had to interrupt his experiments because the <a href="/wiki/World_War_I" title="World War I">World War I</a> and in 1921 he wrote four papers about his work carried out in <a href="/wiki/Bucharest" title="Bucharest">Bucharest</a> and his tests on a diabetic dog. Later that year, he detailed his work by publishing an extensive whitepaper on the effect of the pancreatic extract injected into a diabetic animal, which he called: "Research on the Role of the <a href="/wiki/Pancreas" title="Pancreas">Pancreas</a> in Food Assimilation".<sup id="cite_ref-nrjs_37-0" class="reference"><a href="#cite_note-nrjs-37"><span>[</span>38<span>]</span></a></sup><sup id="cite_ref-nrps_38-0" class="reference"><a href="#cite_note-nrps-38"><span>[</span>39<span>]</span></a></sup></p>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=19" title="Edit section: Extraction and purification in Canada">edit</a>]</span> <span class="mw-headline" id="Extraction_and_purification_in_Canada">Extraction and purification in Canada</span></h3>
<p>In October 1920, Canadian <a href="/wiki/Frederick_Banting" title="Frederick Banting">Frederick Banting</a> was reading one of Minkowski's papers and concluded that it was the very digestive secretions that Minkowski had originally studied that were breaking down the islet secretion(s), thereby making it impossible to extract successfully. He jotted a note to himself: "Ligate pancreatic ducts of the dog. Keep dogs alive till acini degenerate leaving islets. Try to isolate internal secretion of these and relieve glycosurea."</p>
<p>The idea was the pancreas's internal secretion, which, it was supposed, regulates sugar in the bloodstream, might hold the key to the treatment of diabetes. A surgeon by training, Banting knew certain arteries could be tied off that would lead to atrophy of most of the pancreas, while leaving the islets of Langerhans intact. He theorized a relatively pure extract could be made from the islets once most of the rest of pancreas was gone.</p>
<p>In the spring of 1921, Banting traveled to <a href="/wiki/Toronto" title="Toronto">Toronto</a> to explain his idea to <a href="/wiki/John_James_Rickard_Macleod" title="John James Rickard Macleod">J.J.R. Macleod</a>, who was Professor of Physiology at the <a href="/wiki/University_of_Toronto" title="University of Toronto">University of Toronto</a>, and asked Macleod if he could use his lab space to test the idea. Macleod was initially skeptical, but eventually agreed to let Banting use his lab space while he was on holiday for the summer. He also supplied Banting with ten dogs on which to experiment, and two medical students, <a href="/wiki/Charles_Herbert_Best" title="Charles Herbert Best">Charles Best</a> and Clark Noble, to use as lab assistants, before leaving for Scotland. Since Banting required only one lab assistant, Best and Noble flipped a coin to see which would assist Banting for the first half of the summer. Best won the coin toss, and took the first shift as Banting's assistant. Loss of the coin toss may have proved unfortunate for Noble, given that Banting decided to keep Best for the entire summer, and eventually shared half his Nobel Prize money and a large part of the credit for the discovery of insulin with the winner of the toss. Had Noble won the toss, his career might have taken a different path.<sup id="cite_ref-pmid12473641_39-0" class="reference"><a href="#cite_note-pmid12473641-39"><span>[</span>40<span>]</span></a></sup> Banting's method was to tie a <a href="/wiki/Ligature_(medicine)" title="Ligature (medicine)">ligature</a> around the pancreatic duct; when examined several weeks later, the pancreatic digestive cells had died and been absorbed by the immune system, leaving thousands of islets. They then isolated an extract from these islets, producing what they called "isletin" (what we now know as insulin), and tested this extract on the dogs starting July 27.<sup id="cite_ref-Krishnamurthy2002_40-0" class="reference"><a href="#cite_note-Krishnamurthy2002-40"><span>[</span>41<span>]</span></a></sup> Banting and Best were then able to keep a pancreatectomized dog named Marjorie alive for the rest of the summer by injecting her with the crude extract they had prepared. Removal of the pancreas in test animals in essence mimics diabetes, leading to elevated blood glucose levels. Marjorie was able to remain alive because the extracts, containing isletin, were able to lower her blood glucose levels.</p>
<p>Banting and Best presented their results to Macleod on his return to Toronto in the fall of 1921, but Macleod pointed out flaws with the experimental design, and suggested the experiments be repeated with more dogs and better equipment. He then supplied Banting and Best with a better laboratory, and began paying Banting a salary from his research grants. Several weeks later, the second round of experiments was also a success; and Macleod helped publish their results privately in Toronto that November. However, they needed six weeks to extract the isletin, which forced considerable delays. Banting suggested they try to use fetal calf pancreas, which had not yet developed digestive glands; he was relieved to find this method worked well. With the supply problem solved, the next major effort was to purify the extract. In December 1921, Macleod invited the <a href="/wiki/Biochemist" title="Biochemist">biochemist</a> <a href="/wiki/James_Collip" title="James Collip">James Collip</a> to help with this task, and, within a month, the team felt ready for a clinical test.</p>
<p>On January 11, 1922, <a href="/wiki/Leonard_Thompson_(diabetic)" title="Leonard Thompson (diabetic)">Leonard Thompson</a>, a 14-year-old diabetic who lay dying at the <a href="/wiki/Toronto_General_Hospital" title="Toronto General Hospital">Toronto General Hospital</a>, was given the first injection of insulin.<sup id="cite_ref-41" class="reference"><a href="#cite_note-41"><span>[</span>42<span>]</span></a></sup> However, the extract was so impure, Thompson suffered a severe <a href="/wiki/Anaphylaxis" title="Anaphylaxis">allergic reaction</a>, and further injections were canceled. Over the next 12&#160;days, Collip worked day and night to improve the ox-pancreas extract, and a second dose was injected on January 23. This was completely successful, not only in having no obvious side-effects but also in completely eliminating the glycosuria sign of diabetes. The first American patient was <a href="/wiki/Elizabeth_Hughes_Gossett" title="Elizabeth Hughes Gossett">Elizabeth Hughes Gossett</a>, the daughter of the governor of New York.<sup id="cite_ref-miracle_42-0" class="reference"><a href="#cite_note-miracle-42"><span>[</span>43<span>]</span></a></sup> The first patient treated in the U.S. was future woodcut artist <a href="/wiki/James_D._Havens" title="James D. Havens">James D. Havens</a>; Dr. <a href="/wiki/John_Ralston_Williams" title="John Ralston Williams">John Ralston Williams</a> imported insulin from Toronto to <a href="/wiki/Rochester,_New_York" title="Rochester, New York">Rochester, New York</a>, to treat Havens.<sup id="cite_ref-Marcotte_43-0" class="reference"><a href="#cite_note-Marcotte-43"><span>[</span>44<span>]</span></a></sup></p>
<p>Children dying from diabetic ketoacidosis were kept in large wards, often with 50 or more patients in a ward, mostly comatose. Grieving family members were often in attendance, awaiting the (until then, inevitable) death.</p>
<p>In one of medicine's more dramatic moments, Banting, Best, and Collip went from bed to bed, injecting an entire ward with the new purified extract. Before they had reached the last dying child, the first few were awakening from their coma, to the joyous exclamations of their families.<sup id="cite_ref-44" class="reference"><a href="#cite_note-44"><span>[</span>45<span>]</span></a></sup></p>
<p>Banting and Best never worked well with Collip, regarding him as something of an interloper, and Collip left the project soon after.</p>
<p>Over the spring of 1922, Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand, but the preparation remained impure. The drug firm <a href="/wiki/Eli_Lilly_and_Company" title="Eli Lilly and Company">Eli Lilly and Company</a> had offered assistance not long after the first publications in 1921, and they took Lilly up on the offer in April. In November, Lilly made a major breakthrough and were able to produce large quantities of highly refined insulin. Insulin was offered for sale shortly thereafter.</p>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=20" title="Edit section: Synthesis">edit</a>]</span> <span class="mw-headline" id="Synthesis_2">Synthesis</span></h3>
<p>Purified animal-sourced insulin was the only type of insulin available to diabetics until genetic advances occurred later with medical research. The amino acid structure of insulin was characterized in the 1950s,<sup id="cite_ref-Citation_needed.7Cdate.3DMay_2010_45-0" class="reference"><a href="#cite_note-Citation_needed.7Cdate.3DMay_2010-45"><span>[</span>46<span>]</span></a></sup> and the first synthetic insulin was produced simultaneously in the labs of <a href="/wiki/Panayotis_Katsoyannis" title="Panayotis Katsoyannis">Panayotis Katsoyannis</a> at the <a href="/wiki/University_of_Pittsburgh" title="University of Pittsburgh">University of Pittsburgh</a> and <a href="/wiki/Helmut_Zahn" title="Helmut Zahn">Helmut Zahn</a> at <a href="/wiki/RWTH_Aachen" title="RWTH Aachen" class="mw-redirect">RWTH Aachen</a> University in the early 1960s.<sup id="cite_ref-46" class="reference"><a href="#cite_note-46"><span>[</span>47<span>]</span></a></sup><sup id="cite_ref-47" class="reference"><a href="#cite_note-47"><span>[</span>48<span>]</span></a></sup></p>
<p>The first genetically-engineered, synthetic "human" insulin was produced in a laboratory in 1977 by <a href="/wiki/Herbert_Boyer" title="Herbert Boyer">Herbert Boyer</a> using <a href="/wiki/Escherichia_coli" title="Escherichia coli">E. coli</a>.<sup id="cite_ref-urlGenentech_48-0" class="reference"><a href="#cite_note-urlGenentech-48"><span>[</span>49<span>]</span></a></sup><sup id="cite_ref-urlRecombinant_DNA_technology_in_the_synthesis_of_human_insulin_49-0" class="reference"><a href="#cite_note-urlRecombinant_DNA_technology_in_the_synthesis_of_human_insulin-49"><span>[</span>50<span>]</span></a></sup> Partnering with <a href="/wiki/Genentech" title="Genentech">Genentech</a> founded by Boyer, <a href="/wiki/Eli_Lilly_and_Company" title="Eli Lilly and Company">Eli Lilly and Company</a> went on in 1982 to sell the first commercially available biosynthetic human insulin under the brand name <a href="/wiki/Humulin" title="Humulin">Humulin</a>.<sup id="cite_ref-urlRecombinant_DNA_technology_in_the_synthesis_of_human_insulin_49-1" class="reference"><a href="#cite_note-urlRecombinant_DNA_technology_in_the_synthesis_of_human_insulin-49"><span>[</span>50<span>]</span></a></sup> The vast majority of insulin currently used worldwide is now biosynthetic recombinant "human" insulin or its analogues.</p>
<h3><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=21" title="Edit section: Nobel Prizes">edit</a>]</span> <span class="mw-headline" id="Nobel_Prizes">Nobel Prizes</span></h3>
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Frederick Banting joined by Charles Best in office, 1924</div>
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<p>The <a href="/wiki/Nobel_Prize" title="Nobel Prize">Nobel Prize</a> committee in 1923 credited the practical extraction of insulin to a team at the <a href="/wiki/University_of_Toronto" title="University of Toronto">University of Toronto</a> and awarded the Nobel Prize to two men: <a href="/wiki/Frederick_Banting" title="Frederick Banting">Frederick Banting</a> and <a href="/wiki/John_James_Rickard_Macleod" title="John James Rickard Macleod">J.J.R. Macleod</a>.<sup id="cite_ref-urlThe_Nobel_Prize_in_Physiology_or_Medicine_1923_50-0" class="reference"><a href="#cite_note-urlThe_Nobel_Prize_in_Physiology_or_Medicine_1923-50"><span>[</span>51<span>]</span></a></sup> They were awarded the <a href="/wiki/Nobel_Prize_in_Physiology_or_Medicine" title="Nobel Prize in Physiology or Medicine">Nobel Prize in Physiology or Medicine</a> in 1923 for the discovery of insulin. Banting, insulted that Best was not mentioned, shared his prize with him, and Macleod immediately shared his with <a href="/wiki/James_Collip" title="James Collip">James Collip</a>. The patent for insulin was sold to the <a href="/wiki/University_of_Toronto" title="University of Toronto">University of Toronto</a> for one half-dollar.</p>
<p>The <a href="/wiki/Primary_structure" title="Primary structure" class="mw-redirect">primary structure</a> of insulin was determined by British molecular biologist <a href="/wiki/Frederick_Sanger" title="Frederick Sanger">Frederick Sanger</a>.<sup id="cite_ref-Citation_needed.7Cdate.3DMay_2010_45-1" class="reference"><a href="#cite_note-Citation_needed.7Cdate.3DMay_2010-45"><span>[</span>46<span>]</span></a></sup> It was the first protein to have its sequence be determined. He was awarded the 1958 <a href="/wiki/Nobel_Prize_in_Chemistry" title="Nobel Prize in Chemistry">Nobel Prize in Chemistry</a> for this work.</p>
<p>In 1969, after decades of work, <a href="/wiki/Dorothy_Crowfoot_Hodgkin" title="Dorothy Crowfoot Hodgkin" class="mw-redirect">Dorothy Crowfoot Hodgkin</a> determined the spatial conformation of the molecule, the so-called <a href="/wiki/Tertiary_structure" title="Tertiary structure" class="mw-redirect">tertiary structure</a>, by means of <a href="/wiki/X-ray_diffraction" title="X-ray diffraction" class="mw-redirect">X-ray diffraction</a> studies. She had been awarded a Nobel Prize in Chemistry in 1964 for the development of <a href="/wiki/Crystallography" title="Crystallography">crystallography</a>.</p>
<p><a href="/wiki/Rosalyn_Sussman_Yalow" title="Rosalyn Sussman Yalow">Rosalyn Sussman Yalow</a> received the 1977 Nobel Prize in Medicine for the development of the <a href="/wiki/Radioimmunoassay" title="Radioimmunoassay">radioimmunoassay</a> for insulin.</p>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=22" title="Edit section: See also">edit</a>]</span> <span class="mw-headline" id="See_also">See also</span></h2>
<ul>
<li><a href="/wiki/Insulin_analog" title="Insulin analog">Insulin analog</a></li>
<li>Anatomy and physiolology
<ul>
<li><a href="/wiki/Pancreas" title="Pancreas">Pancreas</a></li>
<li><a href="/wiki/Islets_of_Langerhans" title="Islets of Langerhans">Islets of Langerhans</a></li>
<li><a href="/wiki/Endocrinology" title="Endocrinology">Endocrinology</a></li>
<li><a href="/wiki/Leptin#Adiposity_signal" title="Leptin">Leptin</a> (The only other known adiposity signal besides insulin).</li>
</ul>
</li>
<li>Forms of diabetes mellitus
<ul>
<li><a href="/wiki/Diabetes_mellitus" title="Diabetes mellitus">Diabetes mellitus</a></li>
<li><a href="/wiki/Diabetes_mellitus_type_1" title="Diabetes mellitus type 1">Diabetes mellitus type 1</a></li>
<li><a href="/wiki/Diabetes_mellitus_type_2" title="Diabetes mellitus type 2">Diabetes mellitus type 2</a></li>
</ul>
</li>
<li>Treatment
<ul>
<li><a href="/wiki/Diabetic_coma" title="Diabetic coma">Diabetic coma</a></li>
<li><a href="/wiki/Insulin_therapy" title="Insulin therapy">Insulin therapy</a></li>
<li><a href="/wiki/Intensive_insulinotherapy" title="Intensive insulinotherapy">Intensive insulinotherapy</a></li>
<li><a href="/wiki/Insulin_pump" title="Insulin pump">Insulin pump</a></li>
<li><a href="/wiki/Conventional_insulinotherapy" title="Conventional insulinotherapy">Conventional insulinotherapy</a></li>
</ul>
</li>
<li>Other medical / diagnostic uses
<ul>
<li><a href="/wiki/Insulin_tolerance_test" title="Insulin tolerance test">Insulin tolerance test</a></li>
<li><a href="/wiki/Triple_bolus_test" title="Triple bolus test" class="mw-redirect">Triple bolus test</a></li>
</ul>
</li>
</ul>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=23" title="Edit section: References">edit</a>]</span> <span class="mw-headline" id="References">References</span></h2>
<div class="reflist references-column-width" style="-moz-column-width: 35em; -webkit-column-width: 35em; column-width: 35em; list-style-type: decimal;">
<ol class="references">
<li id="cite_note-pmid9235985-0"><b><a href="#cite_ref-pmid9235985_0-0">^</a></b> <span class="reference-text"><a href="/wiki/Protein_Data_Bank" title="Protein Data Bank">PDB</a> <a rel="nofollow" class="external text" href="http://www.rcsb.org/pdb/explore/explore.do?structureId=1ai0">1ai0</a>; <span class="citation Journal">Chang X, Jorgensen AM, Bardrum P, Led JJ (August 1997). "Solution structures of the R6 human insulin hexamer,". <i>Biochemistry</i> <b>36</b> (31): 9409–22. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1021%2Fbi9631069">10.1021/bi9631069</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/9235985">9235985</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Solution+structures+of+the+R6+human+insulin+hexamer%2C&amp;rft.jtitle=Biochemistry&amp;rft.aulast=Chang+X%2C+Jorgensen+AM%2C+Bardrum+P%2C+Led+JJ&amp;rft.au=Chang+X%2C+Jorgensen+AM%2C+Bardrum+P%2C+Led+JJ&amp;rft.date=August+1997&amp;rft.volume=36&amp;rft.issue=31&amp;rft.pages=9409%E2%80%9322&amp;rft_id=info:doi/10.1021%2Fbi9631069&amp;rft_id=info:pmid/9235985&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-pmid15288712-1"><b><a href="#cite_ref-pmid15288712_1-0">^</a></b> <span class="reference-text"><span class="citation Journal">Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W. (November 2004). "Intranasal insulin improves memory in humans.". <i>Psychoneuroendocrinology</i> <b>29</b> (10): 1326–34. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.psyneuen.2004.04.003">10.1016/j.psyneuen.2004.04.003</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/15288712">15288712</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Intranasal+insulin+improves+memory+in+humans.&amp;rft.jtitle=Psychoneuroendocrinology&amp;rft.aulast=Benedict+C%2C+Hallschmid+M%2C+Hatke+A%2C+Schultes+B%2C+Fehm+HL%2C+Born+J%2C+Kern+W.&amp;rft.au=Benedict+C%2C+Hallschmid+M%2C+Hatke+A%2C+Schultes+B%2C+Fehm+HL%2C+Born+J%2C+Kern+W.&amp;rft.date=November+2004&amp;rft.volume=29&amp;rft.issue=10&amp;rft.pages=1326%E2%80%9334&amp;rft_id=info:doi/10.1016%2Fj.psyneuen.2004.04.003&amp;rft_id=info:pmid/15288712&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-pmid20876713-2"><b><a href="#cite_ref-pmid20876713_2-0">^</a></b> <span class="reference-text"><span class="citation Journal">Benedict C, Brede S, Schiöth HB, Lehnert H, Schultes B, Born J, Hallschmid M. (2010). <a rel="nofollow" class="external text" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=3012162">"Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men."</a>. <i>Diabetes</i> <b>60</b> (1): 114–118. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.2337%2Fdb10-0329">10.2337/db10-0329</a>. <a href="/wiki/PubMed_Central" title="PubMed Central">PMC</a>&#160;<a rel="nofollow" class="external text" href="http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=3012162">3012162</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/20876713">20876713</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=3012162">http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=3012162</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Intranasal+insulin+enhances+postprandial+thermogenesis+and+lowers+postprandial+serum+insulin+levels+in+healthy+men.&amp;rft.jtitle=Diabetes&amp;rft.aulast=Benedict+C%2C+Brede+S%2C+Schi%C3%B6th+HB%2C+Lehnert+H%2C+Schultes+B%2C+Born+J%2C+Hallschmid+M.&amp;rft.au=Benedict+C%2C+Brede+S%2C+Schi%C3%B6th+HB%2C+Lehnert+H%2C+Schultes+B%2C+Born+J%2C+Hallschmid+M.&amp;rft.date=2010&amp;rft.volume=60&amp;rft.issue=1&amp;rft.pages=114%E2%80%93118&amp;rft_id=info:doi/10.2337%2Fdb10-0329&amp;rft_id=info:pmc/3012162&amp;rft_id=info:pmid/20876713&amp;rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3D3012162&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-entrez-3">^ <a href="#cite_ref-entrez_3-0"><sup><i><b>a</b></i></sup></a> <a href="#cite_ref-entrez_3-1"><sup><i><b>b</b></i></sup></a> <span class="reference-text"><span class="citation web"><a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&amp;Cmd=ShowDetailView&amp;TermToSearch=3630">"Entrez Gene: INS insulin"</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&amp;Cmd=ShowDetailView&amp;TermToSearch=3630">http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&amp;Cmd=ShowDetailView&amp;TermToSearch=3630</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=bookitem&amp;rft.btitle=Entrez+Gene%3A+INS+insulin&amp;rft.atitle=&amp;rft_id=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fsites%2Fentrez%3FDb%3Dgene%26Cmd%3DShowDetailView%26TermToSearch%3D3630&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-pmid6243748-4"><b><a href="#cite_ref-pmid6243748_4-0">^</a></b> <span class="reference-text"><span class="citation Journal">Bell GI, Pictet RL, Rutter WJ, Cordell B, Tischer E, Goodman HM (March 1980). "Sequence of the human insulin gene". <i>Nature</i> <b>284</b> (5751): 26–32. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1038%2F284026a0">10.1038/284026a0</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/6243748">6243748</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Sequence+of+the+human+insulin+gene&amp;rft.jtitle=Nature&amp;rft.aulast=Bell+GI%2C+Pictet+RL%2C+Rutter+WJ%2C+Cordell+B%2C+Tischer+E%2C+Goodman+HM&amp;rft.au=Bell+GI%2C+Pictet+RL%2C+Rutter+WJ%2C+Cordell+B%2C+Tischer+E%2C+Goodman+HM&amp;rft.date=March+1980&amp;rft.volume=284&amp;rft.issue=5751&amp;rft.pages=26%E2%80%9332&amp;rft_id=info:doi/10.1038%2F284026a0&amp;rft_id=info:pmid/6243748&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-pmid11914736-5"><b><a href="#cite_ref-pmid11914736_5-0">^</a></b> <span class="reference-text"><span class="citation Journal">Melloul D, Marshak S, Cerasi E (2002). "Regulation of insulin gene transcription". <i>Diabetologia</i> <b>45</b> (3): 309–26. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1007%2Fs00125-001-0728-y">10.1007/s00125-001-0728-y</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11914736">11914736</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Regulation+of+insulin+gene+transcription&amp;rft.jtitle=Diabetologia&amp;rft.aulast=Melloul+D%2C+Marshak+S%2C+Cerasi+E&amp;rft.au=Melloul+D%2C+Marshak+S%2C+Cerasi+E&amp;rft.date=2002&amp;rft.volume=45&amp;rft.issue=3&amp;rft.pages=309%E2%80%9326&amp;rft_id=info:doi/10.1007%2Fs00125-001-0728-y&amp;rft_id=info:pmid/11914736&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-pmid17150186-6"><b><a href="#cite_ref-pmid17150186_6-0">^</a></b> <span class="reference-text"><span class="citation Journal">Jang WG, Kim EJ, Park KG, Park YB, Choi HS, Kim HJ, Kim YD, Kim KS, Lee KU, Lee IK (2007). "Glucocorticoid receptor mediated repression of human insulin gene expression is regulated by PGC-1alpha". <i>Biochem. Biophys. Res. Commun.</i> <b>352</b> (3): 716–21. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1016%2Fj.bbrc.2006.11.074">10.1016/j.bbrc.2006.11.074</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17150186">17150186</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Glucocorticoid+receptor+mediated+repression+of+human+insulin+gene+expression+is+regulated+by+PGC-1alpha&amp;rft.jtitle=Biochem.+Biophys.+Res.+Commun.&amp;rft.aulast=Jang+WG%2C+Kim+EJ%2C+Park+KG%2C+Park+YB%2C+Choi+HS%2C+Kim+HJ%2C+Kim+YD%2C+Kim+KS%2C+Lee+KU%2C+Lee+IK&amp;rft.au=Jang+WG%2C+Kim+EJ%2C+Park+KG%2C+Park+YB%2C+Choi+HS%2C+Kim+HJ%2C+Kim+YD%2C+Kim+KS%2C+Lee+KU%2C+Lee+IK&amp;rft.date=2007&amp;rft.volume=352&amp;rft.issue=3&amp;rft.pages=716%E2%80%9321&amp;rft_id=info:doi/10.1016%2Fj.bbrc.2006.11.074&amp;rft_id=info:pmid/17150186&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-sanger-7"><b><a href="#cite_ref-sanger_7-0">^</a></b> <span class="reference-text"><span class="citation Journal">Sanger F, Tuppy H (September 1951). <a rel="nofollow" class="external text" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=1197535">"The amino-acid sequence in the phenylalanyl chain of insulin. I. The identification of lower peptides from partial hydrolysates"</a>. <i>Biochem. J.</i> <b>49</b> (4): 463–81. <a href="/wiki/PubMed_Central" title="PubMed Central">PMC</a>&#160;<a rel="nofollow" class="external text" href="http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=1197535">1197535</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/14886310">14886310</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=1197535">http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=1197535</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=The+amino-acid+sequence+in+the+phenylalanyl+chain+of+insulin.+I.+The+identification+of+lower+peptides+from+partial+hydrolysates&amp;rft.jtitle=Biochem.+J.&amp;rft.aulast=Sanger+F%2C+Tuppy+H&amp;rft.au=Sanger+F%2C+Tuppy+H&amp;rft.date=September+1951&amp;rft.volume=49&amp;rft.issue=4&amp;rft.pages=463%E2%80%9381&amp;rft_id=info:pmc/1197535&amp;rft_id=info:pmid/14886310&amp;rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3D1197535&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span>; <span class="citation Journal">Sanger F, Tuppy H (September 1951). <a rel="nofollow" class="external text" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=1197536">"The amino-acid sequence in the phenylalanyl chain of insulin. 2. The investigation of peptides from enzymic hydrolysates"</a>. <i>Biochem. 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I. The identification of lower peptides from partial hydrolysates"</a>. <i>Biochem. 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<li id="cite_note-22"><b><a href="#cite_ref-22">^</a></b> <span class="reference-text"><span class="citation Journal">Xianjun Fang, Shuang Xing Yu, Yiling Lu, Robert C. Bast, Jr. James R. Woodgett, and Gordon B. Mills (2000). <a rel="nofollow" class="external text" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=17277">"Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A"</a>. <i>Proceedings of the National Academy of Sciences of the United States of America</i> <b>97</b> (22): 11960–11965. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1073%2Fpnas.220413597">10.1073/pnas.220413597</a>. <a href="/wiki/PubMed_Central" title="PubMed Central">PMC</a>&#160;<a rel="nofollow" class="external text" href="http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=17277">17277</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11035810">11035810</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=17277">http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=17277</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Phosphorylation+and+inactivation+of+glycogen+synthase+kinase+3+by+protein+kinase+A&amp;rft.jtitle=Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America&amp;rft.aulast=Xianjun+Fang%2C+Shuang+Xing+Yu%2C+Yiling+Lu%2C+Robert+C.+Bast%2C+Jr.+James+R.+Woodgett%2C+and+Gordon+B.+Mills&amp;rft.au=Xianjun+Fang%2C+Shuang+Xing+Yu%2C+Yiling+Lu%2C+Robert+C.+Bast%2C+Jr.+James+R.+Woodgett%2C+and+Gordon+B.+Mills&amp;rft.date=2000&amp;rft.volume=97&amp;rft.issue=22&amp;rft.pages=11960%E2%80%9311965&amp;rft_id=info:doi/10.1073%2Fpnas.220413597&amp;rft_id=info:pmc/17277&amp;rft_id=info:pmid/11035810&amp;rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3D17277&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
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<li id="cite_note-28"><b><a href="#cite_ref-28">^</a></b> <span class="reference-text"><span class="citation Journal">Benziane B, Chibalin AV (2008). <a rel="nofollow" class="external text" href="http://ajpendo.physiology.org/content/295/3/E553.long">"Frontiers: skeletal muscle sodium pump regulation: a translocation paradigm"</a>. <i>American Journal of Physiology. Endocrinology and Metabolism</i> <b>295</b> (3): E553-8. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1152%2Fajpendo.90261.2008">10.1152/ajpendo.90261.2008</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18430962">18430962</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://ajpendo.physiology.org/content/295/3/E553.long">http://ajpendo.physiology.org/content/295/3/E553.long</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Frontiers%3A+skeletal+muscle+sodium+pump+regulation%3A+a+translocation+paradigm&amp;rft.jtitle=American+Journal+of+Physiology.+Endocrinology+and+Metabolism&amp;rft.aulast=Benziane+B%2C+Chibalin+AV&amp;rft.au=Benziane+B%2C+Chibalin+AV&amp;rft.date=2008&amp;rft.volume=295&amp;rft.issue=3&amp;rft.pages=E553-8&amp;rft_id=info:doi/10.1152%2Fajpendo.90261.2008&amp;rft_id=info:pmid/18430962&amp;rft_id=http%3A%2F%2Fajpendo.physiology.org%2Fcontent%2F295%2F3%2FE553.long&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-29"><b><a href="#cite_ref-29">^</a></b> <span class="reference-text"><span class="citation Journal">Clausen T (2008). <a rel="nofollow" class="external text" href="http://ajpendo.physiology.org/content/295/3/E727.long">"Regulatory role of translocation of Na+-K+ pumps in skeletal muscle: hypothesis or reality?"</a>. <i>American Journal of Physiology. Endocrinology and Metabolism</i> <b>295</b> (3): E727-8. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1152%2Fajpendo.90494.2008">10.1152/ajpendo.90494.2008</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/18775888">18775888</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://ajpendo.physiology.org/content/295/3/E727.long">http://ajpendo.physiology.org/content/295/3/E727.long</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Regulatory+role+of+translocation+of+Na%2B-K%2B+pumps+in+skeletal+muscle%3A+hypothesis+or+reality%3F&amp;rft.jtitle=American+Journal+of+Physiology.+Endocrinology+and+Metabolism&amp;rft.aulast=Clausen+T&amp;rft.au=Clausen+T&amp;rft.date=2008&amp;rft.volume=295&amp;rft.issue=3&amp;rft.pages=E727-8&amp;rft_id=info:doi/10.1152%2Fajpendo.90494.2008&amp;rft_id=info:pmid/18775888&amp;rft_id=http%3A%2F%2Fajpendo.physiology.org%2Fcontent%2F295%2F3%2FE727.long&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-30"><b><a href="#cite_ref-30">^</a></b> <span class="reference-text"><span class="citation Journal">Gupta AK, Clark RV, Kirchner KA (1992). "Effects of insulin on renal sodium excretion". <i>Hypertension</i> <b>19</b> (1 Suppl): 178–182. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/1730458">1730458</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Effects+of+insulin+on+renal+sodium+excretion&amp;rft.jtitle=Hypertension&amp;rft.aulast=Gupta+AK%2C+Clark+RV%2C+Kirchner+KA&amp;rft.au=Gupta+AK%2C+Clark+RV%2C+Kirchner+KA&amp;rft.date=1992&amp;rft.volume=19&amp;rft.issue=1+Suppl&amp;rft.pages=178%E2%80%93182&amp;rft_id=info:pmid/1730458&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-31"><b><a href="#cite_ref-31">^</a></b> <span class="reference-text"><span class="citation Journal">William C. Duckworth, Robert G. Bennett and Frederick G. Hamel (1998). <a rel="nofollow" class="external text" href="http://edrv.endojournals.org/cgi/content/full/19/5/608#F1">"Insulin Degradation: Progress and Potential"</a>. <i>Endocrine Reviews</i> <b>19</b> (5): 608–624. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1210%2Fer.19.5.608">10.1210/er.19.5.608</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/9793760">9793760</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://edrv.endojournals.org/cgi/content/full/19/5/608#F1">http://edrv.endojournals.org/cgi/content/full/19/5/608#F1</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Insulin+Degradation%3A+Progress+and+Potential&amp;rft.jtitle=Endocrine+Reviews&amp;rft.aulast=William+C.+Duckworth%2C+Robert+G.+Bennett+and+Frederick+G.+Hamel&amp;rft.au=William+C.+Duckworth%2C+Robert+G.+Bennett+and+Frederick+G.+Hamel&amp;rft.date=1998&amp;rft.volume=19&amp;rft.issue=5&amp;rft.pages=608%E2%80%93624&amp;rft_id=info:doi/10.1210%2Fer.19.5.608&amp;rft_id=info:pmid/9793760&amp;rft_id=http%3A%2F%2Fedrv.endojournals.org%2Fcgi%2Fcontent%2Ffull%2F19%2F5%2F608%23F1&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-32"><b><a href="#cite_ref-32">^</a></b> <span class="reference-text">Palmer, BF et. al. 2010. "Carbohydrate and insulin metabolism in chronic kidney disease." UpToDate Online, accessed Nov. 13, 2010.</span></li>
<li id="cite_note-33"><b><a href="#cite_ref-33">^</a></b> <span class="reference-text"><a rel="nofollow" class="external text" href="http://www.businessweek.com/magazine/content/07_33/b4046083.htm">From SemBiosys, A New Kind Of Insulin</a> INSIDE WALL STREET By Gene G. Marcial(AUGUST 13, 2007)</span></li>
<li id="cite_note-34"><b><a href="#cite_ref-34">^</a></b> <span class="reference-text"><a rel="nofollow" class="external free" href="http://www.i-sis.org.uk/gmSaffloweHumanPro-Insulin.php">http://www.i-sis.org.uk/gmSaffloweHumanPro-Insulin.php</a></span></li>
<li id="cite_note-35"><b><a href="#cite_ref-35">^</a></b> <span class="reference-text"><a rel="nofollow" class="external text" href="http://profit.ndtv.com/2009/12/11181626/Biocon-may-launch-oral-insulin.html">NDTV Profit December 11, 2009-Biocon May Launch Oral Insulin</a></span></li>
<li id="cite_note-J._Nutrition_92-36"><b><a href="#cite_ref-J._Nutrition_92_36-0">^</a></b> <span class="reference-text"><span class="citation Journal">The American Institute of Nutrition (1967). <a rel="nofollow" class="external text" href="http://jn.nutrition.org/cgi/reprint/92/4/507.pdf">"Proceedings of the Thirty-first Annual Meeting of the American Institute of Nutrition"</a> (PDF). <i>Journal of Nutrition</i> <b>92</b>: 509<span class="printonly">. <a rel="nofollow" class="external free" href="http://jn.nutrition.org/cgi/reprint/92/4/507.pdf">http://jn.nutrition.org/cgi/reprint/92/4/507.pdf</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Proceedings+of+the+Thirty-first+Annual+Meeting+of+the+American+Institute+of+Nutrition&amp;rft.jtitle=Journal+of+Nutrition&amp;rft.aulast=The+American+Institute+of+Nutrition&amp;rft.au=The+American+Institute+of+Nutrition&amp;rft.date=1967&amp;rft.volume=92&amp;rft.pages=509&amp;rft_id=http%3A%2F%2Fjn.nutrition.org%2Fcgi%2Freprint%2F92%2F4%2F507.pdf&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-nrjs-37"><b><a href="#cite_ref-nrjs_37-0">^</a></b> <span class="reference-text"><span class="citation" id="CITEREFPaulesco1921.2C_August_31">Paulesco, N.C. (1921, August 31), "Recherche sur le rôle du pancréas dans l'assimilation nutritive.", <i>Archives Internationales de Physiologie</i> <b>17</b>: 85–103</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Recherche+sur+le+r%C3%B4le+du+pancr%C3%A9as+dans+l%27assimilation+nutritive.&amp;rft.jtitle=Archives+Internationales+de+Physiologie&amp;rft.aulast=Paulesco&amp;rft.aufirst=N.C.&amp;rft.au=Paulesco%2C%26%2332%3BN.C.&amp;rft.date=1921%2C+August+31&amp;rft.volume=17&amp;rft.pages=85%E2%80%93103&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-nrps-38"><b><a href="#cite_ref-nrps_38-0">^</a></b> <span class="reference-text"><span class="citation" id="CITEREFLestradet1997">Lestradet, H. (1997), <a rel="nofollow" class="external text" href="http://www.em-consulte.com/en/article/79613">"Le 75e anniversaire de la découverte de l’insuline."</a>, <i>Diabetes &amp; Metabolism</i> <b>23</b> (1): 112<span class="printonly">, <a rel="nofollow" class="external free" href="http://www.em-consulte.com/en/article/79613">http://www.em-consulte.com/en/article/79613</a></span></span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Le+75e+anniversaire+de+la+d%C3%A9couverte+de+l%E2%80%99insuline.&amp;rft.jtitle=Diabetes+%26+Metabolism&amp;rft.aulast=Lestradet&amp;rft.aufirst=H.&amp;rft.au=Lestradet%2C%26%2332%3BH.&amp;rft.date=1997&amp;rft.volume=23&amp;rft.issue=1&amp;rft.pages=112&amp;rft_id=http%3A%2F%2Fwww.em-consulte.com%2Fen%2Farticle%2F79613&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-pmid12473641-39"><b><a href="#cite_ref-pmid12473641_39-0">^</a></b> <span class="reference-text"><span class="citation Journal">Wright JR (December 2002). <a rel="nofollow" class="external text" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=137361">"Almost famous: E. Clark Noble, the common thread in the discovery of insulin and vinblastine"</a>. <i>CMAJ</i> <b>167</b> (12): 1391–6. <a href="/wiki/PubMed_Central" title="PubMed Central">PMC</a>&#160;<a rel="nofollow" class="external text" href="http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=137361">137361</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/12473641">12473641</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=137361">http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=137361</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Almost+famous%3A+E.+Clark+Noble%2C+the+common+thread+in+the+discovery+of+insulin+and+vinblastine&amp;rft.jtitle=CMAJ&amp;rft.aulast=Wright+JR&amp;rft.au=Wright+JR&amp;rft.date=December+2002&amp;rft.volume=167&amp;rft.issue=12&amp;rft.pages=1391%E2%80%936&amp;rft_id=info:pmc/137361&amp;rft_id=info:pmid/12473641&amp;rft_id=http%3A%2F%2Fwww.pubmedcentral.nih.gov%2Farticlerender.fcgi%3Ftool%3Dpmcentrez%26artid%3D137361&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-Krishnamurthy2002-40"><b><a href="#cite_ref-Krishnamurthy2002_40-0">^</a></b> <span class="reference-text"><span class="citation book">Krishnamurthy, Kalayya (2002). <a rel="nofollow" class="external text" href="http://books.google.com/books?id=dAXYzzDL_9oC&amp;pg=PA266"><i>Pioneers in scientific discoveries</i></a>. Mittal Publications. p.&#160;266. <a href="/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a>&#160;<a href="/wiki/Special:BookSources/9788170998440" title="Special:BookSources/9788170998440">9788170998440</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://books.google.com/books?id=dAXYzzDL_9oC&amp;pg=PA266">http://books.google.com/books?id=dAXYzzDL_9oC&amp;pg=PA266</a></span><span class="reference-accessdate">. Retrieved 26 July 2011</span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Pioneers+in+scientific+discoveries&amp;rft.aulast=Krishnamurthy&amp;rft.aufirst=Kalayya&amp;rft.au=Krishnamurthy%2C%26%2332%3BKalayya&amp;rft.date=2002&amp;rft.pages=p.%26nbsp%3B266&amp;rft.pub=Mittal+Publications&amp;rft.isbn=9788170998440&amp;rft_id=http%3A%2F%2Fbooks.google.com%2Fbooks%3Fid%3DdAXYzzDL_9oC%26pg%3DPA266&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-41"><b><a href="#cite_ref-41">^</a></b> <span class="reference-text"><span class="citation Journal">Bliss, Michael (July 1993). <a rel="nofollow" class="external text" href="http://jhmas.oxfordjournals.org/content/48/3/253.full.pdf">"Rewriting Medical History: Charles Best and the Banting and Best Myth"</a>. <i>Journal of the History of Medicine</i> <b>48</b>: 254. <a href="/wiki/International_Standard_Serial_Number" title="International Standard Serial Number">ISSN</a>&#160;<a rel="nofollow" class="external text" href="http://www.worldcat.org/issn/0022-5045">0022-5045</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://jhmas.oxfordjournals.org/content/48/3/253.full.pdf">http://jhmas.oxfordjournals.org/content/48/3/253.full.pdf</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Rewriting+Medical+History%3A+Charles+Best+and+the+Banting+and+Best+Myth&amp;rft.jtitle=Journal+of+the+History+of+Medicine&amp;rft.aulast=Bliss&amp;rft.aufirst=Michael&amp;rft.au=Bliss%2C%26%2332%3BMichael&amp;rft.date=July+1993&amp;rft.volume=48&amp;rft.pages=254&amp;rft.issn=0022-5045&amp;rft_id=http%3A%2F%2Fjhmas.oxfordjournals.org%2Fcontent%2F48%2F3%2F253.full.pdf&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-miracle-42"><b><a href="#cite_ref-miracle_42-0">^</a></b> <span class="reference-text"><span class="citation news">Abigail Zuger (October 4, 2010). <a rel="nofollow" class="external text" href="http://www.nytimes.com/2010/10/05/health/05insulin.html?_r=1&amp;hp=&amp;pagewanted=all">"Rediscovering the First Miracle Drug"</a>. <i><a href="/wiki/New_York_Times" title="New York Times" class="mw-redirect">New York Times</a></i><span class="printonly">. <a rel="nofollow" class="external free" href="http://www.nytimes.com/2010/10/05/health/05insulin.html?_r=1&amp;hp=&amp;pagewanted=all">http://www.nytimes.com/2010/10/05/health/05insulin.html?_r=1&amp;hp=&amp;pagewanted=all</a></span><span class="reference-accessdate">. Retrieved 2010-10-06</span>. "Elizabeth Hughes was a cheerful, pretty little girl, five feet tall, with straight brown hair and a consuming interest in birds. On Dr. Allen’s diet her weight fell to 65 pounds, then 52 pounds, and then, after an episode of diarrhea that almost killed her in the spring of 1922, 45 pounds. By then she had survived three years, far longer than expected. And then her mother heard the news: Insulin had finally been isolated in Canada."</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Rediscovering+the+First+Miracle+Drug&amp;rft.jtitle=%5B%5BNew+York+Times%5D%5D&amp;rft.aulast=Abigail+Zuger&amp;rft.au=Abigail+Zuger&amp;rft.date=October+4%2C+2010&amp;rft_id=http%3A%2F%2Fwww.nytimes.com%2F2010%2F10%2F05%2Fhealth%2F05insulin.html%3F_r%3D1%26hp%3D%26pagewanted%3Dall&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-Marcotte-43"><b><a href="#cite_ref-Marcotte_43-0">^</a></b> <span class="reference-text"><span class="citation news">Marcotte, Bob (November 22, 2010). <a rel="nofollow" class="external text" href="http://www.webcitation.org/5uRSurOlI">"Rochester's John Williams a man of scientific talents"</a>. <i><a href="/wiki/Democrat_and_Chronicle" title="Democrat and Chronicle">Democrat and Chronicle</a></i>. <a href="/wiki/Gannett_Company" title="Gannett Company">Gannett Company</a> (<a href="/wiki/Rochester,_New_York" title="Rochester, New York">Rochester, New York</a>): pp.&#160;1B, 4B. Archived from <a rel="nofollow" class="external text" href="http://www.democratandchronicle.com/apps/pbcs.dll/article?AID=201011220301">the original</a> on November 22, 2010<span class="printonly">. <a rel="nofollow" class="external free" href="http://www.webcitation.org/5uRSurOlI">http://www.webcitation.org/5uRSurOlI</a></span><span class="reference-accessdate">. Retrieved November 22, 2010</span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Rochester%27s+John+Williams+a+man+of+scientific+talents&amp;rft.jtitle=%5B%5BDemocrat+and+Chronicle%5D%5D&amp;rft.aulast=Marcotte&amp;rft.aufirst=Bob&amp;rft.au=Marcotte%2C%26%2332%3BBob&amp;rft.date=November+22%2C+2010&amp;rft.series=%5B%5BGannett+Company%5D%5D&amp;rft.pages=pp.%26nbsp%3B1B%2C+4B&amp;rft.place=%5B%5BRochester%2C+New+York%5D%5D&amp;rft_id=http%3A%2F%2Fwww.webcitation.org%2F5uRSurOlI&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-44"><b><a href="#cite_ref-44">^</a></b> <span class="reference-text"><a rel="nofollow" class="external text" href="http://www.medicalnewstoday.com/info/diabetes/discoveryofinsulin.php">Medical News Today-Discovery of Insulin</a></span></li>
<li id="cite_note-Citation_needed.7Cdate.3DMay_2010-45">^ <a href="#cite_ref-Citation_needed.7Cdate.3DMay_2010_45-0"><sup><i><b>a</b></i></sup></a> <a href="#cite_ref-Citation_needed.7Cdate.3DMay_2010_45-1"><sup><i><b>b</b></i></sup></a> <span class="reference-text"><sup class="Template-Fact" style="white-space:nowrap;">[<i><a href="/wiki/Wikipedia:Citation_needed" title="Wikipedia:Citation needed"><span title="This claim needs references to reliable sources from May 2010">citation needed</span></a></i>]</sup></span></li>
<li id="cite_note-46"><b><a href="#cite_ref-46">^</a></b> <span class="reference-text"><span class="citation Journal">Goro, Fritz (1964-05-08). <a rel="nofollow" class="external text" href="http://books.google.com/?id=lkEEAAAAMBAJ&amp;lpg=PA47&amp;vq=insulin&amp;pg=PA47#v=onepage&amp;q=insulin">"First Man-made Protein in History"</a>. <i>Life</i> (New York, NY: Time, Inc.) <b>56</b> (19): 47. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1080%2F15216540310001659029">10.1080/15216540310001659029</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/14992380">14992380</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://books.google.com/?id=lkEEAAAAMBAJ&amp;lpg=PA47&amp;vq=insulin&amp;pg=PA47#v=onepage&amp;q=insulin">http://books.google.com/?id=lkEEAAAAMBAJ&amp;lpg=PA47&amp;vq=insulin&amp;pg=PA47#v=onepage&amp;q=insulin</a></span><span class="reference-accessdate">. Retrieved 2009-11-02</span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=First+Man-made+Protein+in+History&amp;rft.jtitle=Life&amp;rft.aulast=Goro&amp;rft.aufirst=Fritz&amp;rft.au=Goro%2C%26%2332%3BFritz&amp;rft.date=1964-05-08&amp;rft.volume=56&amp;rft.issue=19&amp;rft.pages=47&amp;rft.place=New+York%2C+NY&amp;rft.pub=Time%2C+Inc.&amp;rft_id=info:doi/10.1080%2F15216540310001659029&amp;rft_id=info:pmid/14992380&amp;rft_id=http%3A%2F%2Fbooks.google.com%2F%3Fid%3DlkEEAAAAMBAJ%26lpg%3DPA47%26vq%3Dinsulin%26pg%3DPA47%23v%3Donepage%26q%3Dinsulin&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-47"><b><a href="#cite_ref-47">^</a></b> <span class="reference-text"><span class="citation book">Federwisch, Matthias; Dieken, Markus Leyck; De Meyts, Pierre, eds. (2002). <a rel="nofollow" class="external text" href="http://books.google.com/?id=Ula72_FSwy8C&amp;lpg=PP11&amp;dq=Panayotis%20Katsoyannis&amp;pg=PP11#v=onepage&amp;q=Panayotis%20Katsoyannis"><i>Insulin &amp; Related Proteins – Structure to Function and Pharmacology</i></a>. Dordrecht, Netherlands: Kluwer Academic Publishers. pp.&#160;ix. <a href="/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a>&#160;<a href="/wiki/Special:BookSources/1-4020-0655-1" title="Special:BookSources/1-4020-0655-1">1-4020-0655-1</a><span class="printonly">. <a rel="nofollow" class="external free" href="http://books.google.com/?id=Ula72_FSwy8C&amp;lpg=PP11&amp;dq=Panayotis%20Katsoyannis&amp;pg=PP11#v=onepage&amp;q=Panayotis%20Katsoyannis">http://books.google.com/?id=Ula72_FSwy8C&amp;lpg=PP11&amp;dq=Panayotis%20Katsoyannis&amp;pg=PP11#v=onepage&amp;q=Panayotis%20Katsoyannis</a></span><span class="reference-accessdate">. Retrieved 2009-11-02</span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Insulin+%26+Related+Proteins+%E2%80%93+Structure+to+Function+and+Pharmacology&amp;rft.date=2002&amp;rft.pages=pp.%26nbsp%3Bix&amp;rft.place=Dordrecht%2C+Netherlands&amp;rft.pub=Kluwer+Academic+Publishers&amp;rft.isbn=1-4020-0655-1&amp;rft_id=http%3A%2F%2Fbooks.google.com%2F%3Fid%3DUla72_FSwy8C%26lpg%3DPP11%26dq%3DPanayotis%2520Katsoyannis%26pg%3DPP11%23v%3Donepage%26q%3DPanayotis%2520Katsoyannis&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-urlGenentech-48"><b><a href="#cite_ref-urlGenentech_48-0">^</a></b> <span class="reference-text"><span class="citation web"><a rel="nofollow" class="external text" href="http://www.gene.com/gene/news/press-releases/display.do?method=detail&amp;id=4160">"First Successful Laboratory Production of Human Insulin Announced"</a>. <i>News Release</i>. Genentech. 1978-09-06<span class="printonly">. <a rel="nofollow" class="external free" href="http://www.gene.com/gene/news/press-releases/display.do?method=detail&amp;id=4160">http://www.gene.com/gene/news/press-releases/display.do?method=detail&amp;id=4160</a></span><span class="reference-accessdate">. Retrieved 2009-11-03</span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=bookitem&amp;rft.btitle=First+Successful+Laboratory+Production+of+Human+Insulin+Announced&amp;rft.atitle=News+Release&amp;rft.date=1978-09-06&amp;rft.pub=Genentech&amp;rft_id=http%3A%2F%2Fwww.gene.com%2Fgene%2Fnews%2Fpress-releases%2Fdisplay.do%3Fmethod%3Ddetail%26id%3D4160&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-urlRecombinant_DNA_technology_in_the_synthesis_of_human_insulin-49">^ <a href="#cite_ref-urlRecombinant_DNA_technology_in_the_synthesis_of_human_insulin_49-0"><sup><i><b>a</b></i></sup></a> <a href="#cite_ref-urlRecombinant_DNA_technology_in_the_synthesis_of_human_insulin_49-1"><sup><i><b>b</b></i></sup></a> <span class="reference-text"><span class="citation web">Tof I (1994). <a rel="nofollow" class="external text" href="http://www.littletree.com.au/dna.htm">"Recombinant DNA technology in the synthesis of human insulin"</a>. Little Tree Publishing<span class="printonly">. <a rel="nofollow" class="external free" href="http://www.littletree.com.au/dna.htm">http://www.littletree.com.au/dna.htm</a></span><span class="reference-accessdate">. Retrieved 2009-11-03</span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=bookitem&amp;rft.btitle=Recombinant+DNA+technology+in+the+synthesis+of+human+insulin&amp;rft.atitle=&amp;rft.aulast=Tof+I&amp;rft.au=Tof+I&amp;rft.date=1994&amp;rft.pub=Little+Tree+Publishing&amp;rft_id=http%3A%2F%2Fwww.littletree.com.au%2Fdna.htm&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
<li id="cite_note-urlThe_Nobel_Prize_in_Physiology_or_Medicine_1923-50"><b><a href="#cite_ref-urlThe_Nobel_Prize_in_Physiology_or_Medicine_1923_50-0">^</a></b> <span class="reference-text"><span class="citation web"><a rel="nofollow" class="external text" href="http://nobelprize.org/nobel_prizes/medicine/laureates/1923/">"The Nobel Prize in Physiology or Medicine 1923"</a>. The Nobel Foundation<span class="printonly">. <a rel="nofollow" class="external free" href="http://nobelprize.org/nobel_prizes/medicine/laureates/1923/">http://nobelprize.org/nobel_prizes/medicine/laureates/1923/</a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=bookitem&amp;rft.btitle=The+Nobel+Prize+in+Physiology+or+Medicine+1923&amp;rft.atitle=&amp;rft.pub=The+Nobel+Foundation&amp;rft_id=http%3A%2F%2Fnobelprize.org%2Fnobel_prizes%2Fmedicine%2Flaureates%2F1923%2F&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></span></li>
</ol>
</div>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=24" title="Edit section: Further reading">edit</a>]</span> <span class="mw-headline" id="Further_reading">Further reading</span></h2>
<div class="refbegin references-column-width" style="-moz-column-width: 35em; -webkit-column-width: 35em; column-width: 35em;">
<ul>
<li><span class="citation book">Reaven, Gerald M.; Ami Laws (ed.) (1999--04-15). <i>Insulin Resistance: The Metabolic Syndrome X</i> (1st ed.). Totowa, New Jersey: Humana Press. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1226%2F0896035883">10.1226/0896035883</a>. <a href="/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a>&#160;<a href="/wiki/Special:BookSources/0-89603-588-3" title="Special:BookSources/0-89603-588-3">0-89603-588-3</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Insulin+Resistance%3A+The+Metabolic+Syndrome+X&amp;rft.aulast=Reaven&amp;rft.aufirst=Gerald+M.&amp;rft.au=Reaven%2C%26%2332%3BGerald+M.&amp;rft.date=1999--04-15&amp;rft.edition=1st&amp;rft.place=Totowa%2C+New+Jersey&amp;rft.pub=Humana+Press&amp;rft_id=info:doi/10.1226%2F0896035883&amp;rft.isbn=0-89603-588-3&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></li>
<li><span class="citation book">Leahy, Jack L.; William T. Cefalu (ed.) (2002-03-22). <i>Insulin Therapy</i> (1st ed.). New York: Marcel Dekker. <a href="/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a>&#160;<a href="/wiki/Special:BookSources/0-8247-0711-7" title="Special:BookSources/0-8247-0711-7">0-8247-0711-7</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Insulin+Therapy&amp;rft.aulast=Leahy&amp;rft.aufirst=Jack+L.&amp;rft.au=Leahy%2C%26%2332%3BJack+L.&amp;rft.date=2002-03-22&amp;rft.edition=1st&amp;rft.place=New+York&amp;rft.pub=Marcel+Dekker&amp;rft.isbn=0-8247-0711-7&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></li>
<li><span class="citation book">Kumar, Sudhesh; Stephen O'Rahilly (ed.) (2005-01-14). <i>Insulin Resistance: Insulin Action and Its Disturbances in Disease</i>. Chichester, England: Wiley. <a href="/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a>&#160;<a href="/wiki/Special:BookSources/0-470-85008-6" title="Special:BookSources/0-470-85008-6">0-470-85008-6</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Insulin+Resistance%3A+Insulin+Action+and+Its+Disturbances+in+Disease&amp;rft.aulast=Kumar&amp;rft.aufirst=Sudhesh&amp;rft.au=Kumar%2C%26%2332%3BSudhesh&amp;rft.date=2005-01-14&amp;rft.place=Chichester%2C+England&amp;rft.pub=Wiley&amp;rft.isbn=0-470-85008-6&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></li>
<li><span class="citation book">Ehrlich, Ann; Carol L. Schroeder (2000-06-16). <i>Medical Terminology for Health Professions</i> (4th ed.). Thomson Delmar Learning. <a href="/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a>&#160;<a href="/wiki/Special:BookSources/0-7668-1297-9" title="Special:BookSources/0-7668-1297-9">0-7668-1297-9</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Medical+Terminology+for+Health+Professions&amp;rft.aulast=Ehrlich&amp;rft.aufirst=Ann&amp;rft.au=Ehrlich%2C%26%2332%3BAnn&amp;rft.date=2000-06-16&amp;rft.edition=4th&amp;rft.pub=Thomson+Delmar+Learning&amp;rft.isbn=0-7668-1297-9&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></li>
<li><span class="citation book">Draznin, Boris; <a href="/wiki/Derek_LeRoith" title="Derek LeRoith">Derek LeRoith</a> (September 1994). <i>Molecular Biology of Diabetes: Autoimmunity and Genetics; Insulin Synthesis and Secretion</i>. Totowa, New Jersey: Humana Press. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.1226%2F0896032868">10.1226/0896032868</a>. <a href="/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a>&#160;<a href="/wiki/Special:BookSources/0-89603-286-8" title="Special:BookSources/0-89603-286-8">0-89603-286-8</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Molecular+Biology+of+Diabetes%3A+Autoimmunity+and+Genetics%3B+Insulin+Synthesis+and+Secretion&amp;rft.aulast=Draznin&amp;rft.aufirst=Boris&amp;rft.au=Draznin%2C%26%2332%3BBoris&amp;rft.date=September+1994&amp;rft.place=Totowa%2C+New+Jersey&amp;rft.pub=Humana+Press&amp;rft_id=info:doi/10.1226%2F0896032868&amp;rft.isbn=0-89603-286-8&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></li>
<li><a rel="nofollow" class="external text" href="http://www.collectionscanada.ca/physicians/002032-200-e.html">Famous Canadian Physicians: Sir Frederick Banting</a> at Library and Archives Canada</li>
<li><span class="citation Journal">McKeage K, Goa KL (2001). "Insulin glargine: a review of its therapeutic use as a long-acting agent for the management of type 1 and 2 diabetes mellitus". <i>Drugs</i> <b>61</b> (11): 1599–624. <a href="/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a rel="nofollow" class="external text" href="http://dx.doi.org/10.2165%2F00003495-200161110-00007">10.2165/00003495-200161110-00007</a>. <a href="/wiki/PubMed_Identifier" title="PubMed Identifier" class="mw-redirect">PMID</a>&#160;<a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/11577797">11577797</a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Insulin+glargine%3A+a+review+of+its+therapeutic+use+as+a+long-acting+agent+for+the+management+of+type+1+and+2+diabetes+mellitus&amp;rft.jtitle=Drugs&amp;rft.aulast=McKeage+K%2C+Goa+KL&amp;rft.au=McKeage+K%2C+Goa+KL&amp;rft.date=2001&amp;rft.volume=61&amp;rft.issue=11&amp;rft.pages=1599%E2%80%93624&amp;rft_id=info:doi/10.2165%2F00003495-200161110-00007&amp;rft_id=info:pmid/11577797&amp;rfr_id=info:sid/en.wikipedia.org:Insulin"><span style="display: none;">&#160;</span></span></li>
</ul>
</div>
<h2><span class="editsection">[<a href="/w/index.php?title=Insulin&amp;action=edit&amp;section=25" title="Edit section: External links">edit</a>]</span> <span class="mw-headline" id="External_links">External links</span></h2>
<div class="column-width" style="-moz-column-width: 35em; -webkit-column-width: 35em; column-width: 35em;">
<ul>
<li><a rel="nofollow" class="external text" href="http://macromoleculeinsights.com/insulin.php">The Insulin Protein</a></li>
<li><a rel="nofollow" class="external text" href="http://www.dailytimes.com.pk/default.asp?page=2006%5C07%5C15%5Cstory_15-7-2006_pg3_2">Inspired by Insulin</a> article by parent of a diabetic child</li>
<li><a rel="nofollow" class="external text" href="http://www.vega.org.uk/video/programme/18">Frederick Sanger, Nobel Prize for sequencing Insulin</a> Freeview video with John Sanger and John Walker by the Vega Science Trust.</li>
<li><a rel="nofollow" class="external text" href="http://nist.rcsb.org/pdb/molecules/pdb14_1.html">Insulin: entry from protein databank</a></li>
<li><a rel="nofollow" class="external text" href="http://www.med.uni-giessen.de/itr/history/inshist.html">The History of Insulin</a></li>
<li><a rel="nofollow" class="external text" href="http://www.rxlist.com/cgi/generic/insulinlispro.htm">Insulin Lispro</a></li>
<li><a rel="nofollow" class="external text" href="http://archives.cbc.ca/IDD-1-75-702/science_technology/diabetes/">CBC Digital Archives - Banting, Best, Macleod, Collip: Chasing a Cure for Diabetes</a></li>
<li><a rel="nofollow" class="external text" href="http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&amp;part=dmn">GeneReviews/NCBI/NIH/UW entry on Permanent Neonatal Diabetes Mellitus</a></li>
<li><a rel="nofollow" class="external text" href="http://www.cosmosmagazine.com/node/663"><i>Cosmos Magazine</i>: Insulin mystery cracked after 20&#160;years</a></li>
<li><a rel="nofollow" class="external text" href="http://diabetes.niddk.nih.gov/">National Diabetes Information Clearinghouse</a></li>
<li><a rel="nofollow" class="external text" href="http://link.library.utoronto.ca/insulin/">Discovery and Early Development of Insulin, 1920–1925</a></li>
<li><a rel="nofollow" class="external text" href="http://www.medbio.info/Horn/Time%203-4/secretion_of_insulin_and_glucagon_nov_2007.htm">Secretion of Insulin and Glucagon</a></li>
<li><a rel="nofollow" class="external text" href="http://www.northcoastmed.com/newsletter/news001.htm">Insulin Types Comparison Chart</a></li>
<li><a rel="nofollow" class="external text" href="http://www.steroiduse.org/hormones/78-the-insulin-hormone.html">Insulin hormone dosage and side effects</a></li>
<li><a rel="nofollow" class="external text" href="http://www.rounite.com/2008/09/12/nicolae-paulescu/">The True Discoverer of Insulin - Nicolae Paulescu</a></li>
<li><a rel="nofollow" class="external text" href="http://www.genome.jp/kegg-bin/show_pathway?hsa04910+3630">Insulin signaling pathway</a></li>
<li><a rel="nofollow" class="external text" href="http://www.lifesci.dundee.ac.uk/people/kei_sakamoto/research/">Molecular Physiology of Signalling Proteins</a></li>
<li><a rel="nofollow" class="external text" href="http://www.aboutkidshealth.ca/En/ResourceCentres/Diabetes/AboutDiabetes/Pages/Insulin-An-Overview.aspx">Animations of insulin's action in the body</a> at AboutKidsHealth.ca</li>
</ul>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1ev6_EBI.jpg" class="image" title="1ev6: Structure of the monoclinic form of the M-cresol/insulin R6 hexamer"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/6/6c/PDB_1ev6_EBI.jpg/180px-PDB_1ev6_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
</div>
</td>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1ev6</b>: Structure of the monoclinic form of the M-cresol/insulin R6 hexamer &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1evr_EBI.jpg" class="image" title="1evr: The structure of the resorcinol/insulin R6 hexamer"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/4/46/PDB_1evr_EBI.jpg/180px-PDB_1evr_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1evr</b>: The structure of the resorcinol/insulin R6 hexamer &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1fu2_EBI.jpg" class="image" title="1fu2: FIRST PROTEIN STRUCTURE DETERMINED FROM X-RAY POWDER DIFFRACTION DATA"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/3/3e/PDB_1fu2_EBI.jpg/180px-PDB_1fu2_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
</div>
</td>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1fu2</b>: FIRST PROTEIN STRUCTURE DETERMINED FROM X-RAY POWDER DIFFRACTION DATA &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1fub_EBI.jpg" class="image" title="1fub: FIRST PROTEIN STRUCTURE DETERMINED FROM X-RAY POWDER DIFFRACTION DATA"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/3/36/PDB_1fub_EBI.jpg/180px-PDB_1fub_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
</div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1fub</b>: FIRST PROTEIN STRUCTURE DETERMINED FROM X-RAY POWDER DIFFRACTION DATA &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1g7a_EBI.jpg" class="image" title="1g7a: 1.2 A structure of T3R3 human insulin at 100 K"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/9/9c/PDB_1g7a_EBI.jpg/180px-PDB_1g7a_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1g7a</b>: 1.2 A structure of T3R3 human insulin at 100 K &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1g7b_EBI.jpg" class="image" title="1g7b: 1.3 A STRUCTURE OF T3R3 HUMAN INSULIN AT 100 K"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/3/3b/PDB_1g7b_EBI.jpg/180px-PDB_1g7b_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1g7b</b>: 1.3 A STRUCTURE OF T3R3 HUMAN INSULIN AT 100 K &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1guj_EBI.jpg" class="image" title="1guj: INSULIN AT PH 2: STRUCTURAL ANALYSIS OF THE CONDITIONS PROMOTING INSULIN FIBRE FORMATION."><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/6/68/PDB_1guj_EBI.jpg/180px-PDB_1guj_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1guj</b>: INSULIN AT PH 2: STRUCTURAL ANALYSIS OF THE CONDITIONS PROMOTING INSULIN FIBRE FORMATION. &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1hiq_EBI.jpg" class="image" title="1hiq: PARADOXICAL STRUCTURE AND FUNCTION IN A MUTANT HUMAN INSULIN ASSOCIATED WITH DIABETES MELLITUS"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/6/60/PDB_1hiq_EBI.jpg/180px-PDB_1hiq_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1hiq</b>: PARADOXICAL STRUCTURE AND FUNCTION IN A MUTANT HUMAN INSULIN ASSOCIATED WITH DIABETES MELLITUS &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1hit_EBI.jpg" class="image" title="1hit: RECEPTOR BINDING REDEFINED BY A STRUCTURAL SWITCH IN A MUTANT HUMAN INSULIN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/b/b7/PDB_1hit_EBI.jpg/180px-PDB_1hit_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1hit</b>: RECEPTOR BINDING REDEFINED BY A STRUCTURAL SWITCH IN A MUTANT HUMAN INSULIN &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1hls_EBI.jpg" class="image" title="1hls: NMR STRUCTURE OF THE HUMAN INSULIN-HIS(B16)"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/d/de/PDB_1hls_EBI.jpg/180px-PDB_1hls_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
</div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1hls</b>: NMR STRUCTURE OF THE HUMAN INSULIN-HIS(B16) &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1htv_EBI.jpg" class="image" title="1htv: CRYSTAL STRUCTURE OF DESTRIPEPTIDE (B28-B30) INSULIN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/1/11/PDB_1htv_EBI.jpg/180px-PDB_1htv_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1htv</b>: CRYSTAL STRUCTURE OF DESTRIPEPTIDE (B28-B30) INSULIN &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1iza_EBI.jpg" class="image" title="1iza: ROLE OF B13 GLU IN INSULIN ASSEMBLY: THE HEXAMER STRUCTURE OF RECOMBINANT MUTANT (B13 GLU-&gt; GLN) INSULIN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/c/c1/PDB_1iza_EBI.jpg/180px-PDB_1iza_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1iza</b>: ROLE OF B13 GLU IN INSULIN ASSEMBLY: THE HEXAMER STRUCTURE OF RECOMBINANT MUTANT (B13 GLU-&gt; GLN) INSULIN &#160;</div>
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</table>
<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
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<div class="floatnone"><a href="/wiki/File:PDB_1izb_EBI.jpg" class="image" title="1izb: ROLE OF B13 GLU IN INSULIN ASSEMBLY: THE HEXAMER STRUCTURE OF RECOMBINANT MUTANT (B13 GLU-&gt; GLN) INSULIN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/2/2f/PDB_1izb_EBI.jpg/180px-PDB_1izb_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1izb</b>: ROLE OF B13 GLU IN INSULIN ASSEMBLY: THE HEXAMER STRUCTURE OF RECOMBINANT MUTANT (B13 GLU-&gt; GLN) INSULIN &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1j73_EBI.jpg" class="image" title="1j73: Crystal structure of an unstable insulin analog with native activity."><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/e/e1/PDB_1j73_EBI.jpg/180px-PDB_1j73_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1j73</b>: Crystal structure of an unstable insulin analog with native activity. &#160;</div>
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</table>
<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1jca_EBI.jpg" class="image" title="1jca: Non-standard Design of Unstable Insulin Analogues with Enhanced Activity"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/4/48/PDB_1jca_EBI.jpg/180px-PDB_1jca_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1jca</b>: Non-standard Design of Unstable Insulin Analogues with Enhanced Activity &#160;</div>
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</table>
<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1jco_EBI.jpg" class="image" title="1jco: Solution structure of the monomeric [Thr(B27)-&gt;Pro,Pro(B28)-&gt;Thr] insulin mutant (PT insulin)"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/9/9a/PDB_1jco_EBI.jpg/180px-PDB_1jco_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1jco</b>: Solution structure of the monomeric [Thr(B27)-&gt;Pro,Pro(B28)-&gt;Thr] insulin mutant (PT insulin) &#160;</div>
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</table>
<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1lph_EBI.jpg" class="image" title="1lph: LYS(B28)PRO(B29)-HUMAN INSULIN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/6/6e/PDB_1lph_EBI.jpg/180px-PDB_1lph_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1lph</b>: LYS(B28)PRO(B29)-HUMAN INSULIN &#160;</div>
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<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_1m5a_EBI.jpg" class="image" title="1m5a: Crystal Structure of 2-Co(2+)-Insulin at 1.2A Resolution"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/e/ee/PDB_1m5a_EBI.jpg/180px-PDB_1m5a_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1m5a</b>: Crystal Structure of 2-Co(2+)-Insulin at 1.2A Resolution &#160;</div>
</td>
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</table>
<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
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<div class="floatnone"><a href="/wiki/File:PDB_1mhi_EBI.jpg" class="image" title="1mhi: THREE-DIMENSIONAL SOLUTION STRUCTURE OF AN INSULIN DIMER. A STUDY OF THE B9(ASP) MUTANT OF HUMAN INSULIN USING NUCLEAR MAGNETIC RESONANCE DISTANCE GEOMETRY AND RESTRAINED MOLECULAR DYNAMICS"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/6/68/PDB_1mhi_EBI.jpg/180px-PDB_1mhi_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<div class="floatnone"><a href="/wiki/File:PDB_1xda_EBI.jpg" class="image" title="1xda: STRUCTURE OF INSULIN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/0/0c/PDB_1xda_EBI.jpg/180px-PDB_1xda_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1xda</b>: STRUCTURE OF INSULIN &#160;</div>
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<div class="floatnone"><a href="/wiki/File:PDB_1xgl_EBI.jpg" class="image" title="1xgl: HUMAN INSULIN DISULFIDE ISOMER, NMR, 10 STRUCTURES"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/4/47/PDB_1xgl_EBI.jpg/180px-PDB_1xgl_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<div class="floatnone"><a href="/wiki/File:PDB_1xw7_EBI.png" class="image" title="1xw7: Diabetes-Associated Mutations in Human Insulin: Crystal Structure and Photo-Cross-Linking Studies of A-Chain Variant Insulin Wakayama"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/c/c4/PDB_1xw7_EBI.png/180px-PDB_1xw7_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
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<div class="floatnone"><a href="/wiki/File:PDB_1zeg_EBI.jpg" class="image" title="1zeg: STRUCTURE OF B28 ASP INSULIN IN COMPLEX WITH PHENOL"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/f/f5/PDB_1zeg_EBI.jpg/180px-PDB_1zeg_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1zeg</b>: STRUCTURE OF B28 ASP INSULIN IN COMPLEX WITH PHENOL &#160;</div>
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<div class="floatnone"><a href="/wiki/File:PDB_1zeh_EBI.jpg" class="image" title="1zeh: STRUCTURE OF INSULIN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/d/df/PDB_1zeh_EBI.jpg/180px-PDB_1zeh_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1zeh</b>: STRUCTURE OF INSULIN &#160;</div>
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<div class="floatnone"><a href="/wiki/File:PDB_1zni_EBI.jpg" class="image" title="1zni: INSULIN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/e/ed/PDB_1zni_EBI.jpg/180px-PDB_1zni_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1zni</b>: INSULIN &#160;</div>
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<div class="floatnone"><a href="/wiki/File:PDB_1znj_EBI.jpg" class="image" title="1znj: INSULIN, MONOCLINIC CRYSTAL FORM"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/7/7b/PDB_1znj_EBI.jpg/180px-PDB_1znj_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>1znj</b>: INSULIN, MONOCLINIC CRYSTAL FORM &#160;</div>
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<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2a3g_EBI.png" class="image" title="2a3g: The structure of T6 bovine insulin"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/c/c7/PDB_2a3g_EBI.png/180px-PDB_2a3g_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
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<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2a3g</b>: The structure of T6 bovine insulin &#160;</div>
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<div class="floatnone"><a href="/wiki/File:PDB_2aiy_EBI.jpg" class="image" title="2aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 20 STRUCTURES"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/2/23/PDB_2aiy_EBI.jpg/180px-PDB_2aiy_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2aiy</b>: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 20 STRUCTURES &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2bn1_EBI.png" class="image" title="2bn1: INSULIN AFTER A HIGH DOSE X-RAY BURN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/e/e1/PDB_2bn1_EBI.png/180px-PDB_2bn1_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2bn1</b>: INSULIN AFTER A HIGH DOSE X-RAY BURN &#160;</div>
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<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2bn3_EBI.png" class="image" title="2bn3: INSULIN BEFORE A HIGH DOSE X-RAY BURN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/1/15/PDB_2bn3_EBI.png/180px-PDB_2bn3_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
</div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2bn3</b>: INSULIN BEFORE A HIGH DOSE X-RAY BURN &#160;</div>
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<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2c8q_EBI.png" class="image" title="2c8q: INSULINE(1SEC) AND UV LASER EXCITED FLUORESCENCE"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/b/bd/PDB_2c8q_EBI.png/180px-PDB_2c8q_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
</div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2c8q</b>: INSULINE(1SEC) AND UV LASER EXCITED FLUORESCENCE &#160;</div>
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<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2c8r_EBI.png" class="image" title="2c8r: INSULINE(60SEC) AND UV LASER EXCITED FLUORESCENCE"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/c/c9/PDB_2c8r_EBI.png/180px-PDB_2c8r_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
</div>
</td>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2c8r</b>: INSULINE(60SEC) AND UV LASER EXCITED FLUORESCENCE &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2g4m_EBI.png" class="image" title="2g4m: Insulin collected at 2.0 A wavelength"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/PDB_2g4m_EBI.png/180px-PDB_2g4m_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
</div>
</td>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2g4m</b>: Insulin collected at 2.0 A wavelength &#160;</div>
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</table>
<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2g54_EBI.png" class="image" title="2g54: Crystal structure of Zn-bound human insulin-degrading enzyme in complex with insulin B chain"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/9/99/PDB_2g54_EBI.png/180px-PDB_2g54_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
</div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2g54</b>: Crystal structure of Zn-bound human insulin-degrading enzyme in complex with insulin B chain &#160;</div>
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</table>
<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2g56_EBI.png" class="image" title="2g56: crystal structure of human insulin-degrading enzyme in complex with insulin B chain"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/a/a0/PDB_2g56_EBI.png/180px-PDB_2g56_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2g56</b>: crystal structure of human insulin-degrading enzyme in complex with insulin B chain &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2hiu_EBI.jpg" class="image" title="2hiu: NMR STRUCTURE OF HUMAN INSULIN IN 20% ACETIC ACID, ZINC-FREE, 10 STRUCTURES"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/9/94/PDB_2hiu_EBI.jpg/180px-PDB_2hiu_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2hiu</b>: NMR STRUCTURE OF HUMAN INSULIN IN 20% ACETIC ACID, ZINC-FREE, 10 STRUCTURES &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2ins_EBI.jpg" class="image" title="2ins: THE STRUCTURE OF DES-PHE B1 BOVINE INSULIN"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/7/7e/PDB_2ins_EBI.jpg/180px-PDB_2ins_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
</div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2ins</b>: THE STRUCTURE OF DES-PHE B1 BOVINE INSULIN &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2omg_EBI.png" class="image" title="2omg: Structure of human insulin cocrystallized with protamine and urea"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/d/d2/PDB_2omg_EBI.png/180px-PDB_2omg_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
</div>
</td>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2omg</b>: Structure of human insulin cocrystallized with protamine and urea &#160;</div>
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</table>
<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
<tr>
<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2omh_EBI.png" class="image" title="2omh: Structure of human insulin cocrystallized with ARG-12 peptide in presence of urea"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/6/67/PDB_2omh_EBI.png/180px-PDB_2omh_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2omh</b>: Structure of human insulin cocrystallized with ARG-12 peptide in presence of urea &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2omi_EBI.png" class="image" title="2omi: Structure of human insulin cocrystallized with protamine"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/c/c4/PDB_2omi_EBI.png/180px-PDB_2omi_EBI.png" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2omi</b>: Structure of human insulin cocrystallized with protamine &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_2tci_EBI.jpg" class="image" title="2tci: X-RAY CRYSTALLOGRAPHIC STUDIES ON HEXAMERIC INSULINS IN THE PRESENCE OF HELIX-STABILIZING AGENTS, THIOCYANATE, METHYLPARABEN AND PHENOL"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/8/85/PDB_2tci_EBI.jpg/180px-PDB_2tci_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>2tci</b>: X-RAY CRYSTALLOGRAPHIC STUDIES ON HEXAMERIC INSULINS IN THE PRESENCE OF HELIX-STABILIZING AGENTS, THIOCYANATE, METHYLPARABEN AND PHENOL &#160;</div>
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_3aiy_EBI.jpg" class="image" title="3aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, REFINED AVERAGE STRUCTURE"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/3/31/PDB_3aiy_EBI.jpg/180px-PDB_3aiy_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>3aiy</b>: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, REFINED AVERAGE STRUCTURE &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_3ins_EBI.jpg" class="image" title="3ins: STRUCTURE OF INSULIN. RESULTS OF JOINT NEUTRON AND X-RAY REFINEMENT"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/c/c8/PDB_3ins_EBI.jpg/180px-PDB_3ins_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
</div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>3ins</b>: STRUCTURE OF INSULIN. RESULTS OF JOINT NEUTRON AND X-RAY REFINEMENT &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_3mth_EBI.jpg" class="image" title="3mth: X-RAY CRYSTALLOGRAPHIC STUDIES ON HEXAMERIC INSULINS IN THE PRESENCE OF HELIX-STABILIZING AGENTS, THIOCYANATE, METHYLPARABEN AND PHENOL"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/c/c6/PDB_3mth_EBI.jpg/180px-PDB_3mth_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
</div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>3mth</b>: X-RAY CRYSTALLOGRAPHIC STUDIES ON HEXAMERIC INSULINS IN THE PRESENCE OF HELIX-STABILIZING AGENTS, THIOCYANATE, METHYLPARABEN AND PHENOL &#160;</div>
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_4aiy_EBI.jpg" class="image" title="4aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 'GREEN' SUBSTATE, AVERAGE STRUCTURE"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/1/1d/PDB_4aiy_EBI.jpg/180px-PDB_4aiy_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>4aiy</b>: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 'GREEN' SUBSTATE, AVERAGE STRUCTURE &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_4ins_EBI.jpg" class="image" title="4ins: THE STRUCTURE OF 2ZN PIG INSULIN CRYSTALS AT 1.5 ANGSTROMS RESOLUTION"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/9/95/PDB_4ins_EBI.jpg/180px-PDB_4ins_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>4ins</b>: THE STRUCTURE OF 2ZN PIG INSULIN CRYSTALS AT 1.5 ANGSTROMS RESOLUTION &#160;</div>
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<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_5aiy_EBI.jpg" class="image" title="5aiy: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 'RED' SUBSTATE, AVERAGE STRUCTURE"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/4/4c/PDB_5aiy_EBI.jpg/180px-PDB_5aiy_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>5aiy</b>: R6 HUMAN INSULIN HEXAMER (SYMMETRIC), NMR, 'RED' SUBSTATE, AVERAGE STRUCTURE &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_6ins_EBI.jpg" class="image" title="6ins: X-RAY ANALYSIS OF THE SINGLE CHAIN /B29-A1$ PEPTIDE-LINKED INSULIN MOLECULE. A COMPLETELY INACTIVE ANALOGUE"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/7/7f/PDB_6ins_EBI.jpg/180px-PDB_6ins_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>6ins</b>: X-RAY ANALYSIS OF THE SINGLE CHAIN /B29-A1$ PEPTIDE-LINKED INSULIN MOLECULE. A COMPLETELY INACTIVE ANALOGUE &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_7ins_EBI.jpg" class="image" title="7ins: STRUCTURE OF PORCINE INSULIN COCRYSTALLIZED WITH CLUPEINE Z"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/5/5e/PDB_7ins_EBI.jpg/180px-PDB_7ins_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
</div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>7ins</b>: STRUCTURE OF PORCINE INSULIN COCRYSTALLIZED WITH CLUPEINE Z &#160;</div>
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<table style="width:200px; float:left; border-collapse:collapse; margin:3px; background-color:#f8f8f8;">
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<td style="height:200px; border:1px solid #CCCCCC; padding:0px;">
<div class="center">
<div class="floatnone"><a href="/wiki/File:PDB_9ins_EBI.jpg" class="image" title="9ins: MONOVALENT CATION BINDING IN CUBIC INSULIN CRYSTALS"><img alt="" src="//upload.wikimedia.org/wikipedia/commons/thumb/1/13/PDB_9ins_EBI.jpg/180px-PDB_9ins_EBI.jpg" width="180" height="135" class="thumbborder" /></a></div>
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<tr style="border-right:1px solid #F0F0F0; border-bottom:1px solid #f0f0f0; border-left:1px solid #f0f0f0; vertical-align:top;">
<td style="display:block; font-size:1em; height:6.2em; padding:0px;">
<div class="gallerytext" style="height:6.1em; width:187px; line-height:1.3em; padding:2px 6px 1px 6px; overflow-y:auto; margin:0px; border:none; border-width:0px;"><b>9ins</b>: MONOVALENT CATION BINDING IN CUBIC INSULIN CRYSTALS &#160;</div>
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<div class="" style="font-size:110%;"><a href="/wiki/Endocrine_system" title="Endocrine system">Endocrine system</a>: <a href="/wiki/Hormone" title="Hormone">hormones</a> (<i><a href="/wiki/Peptide_hormone" title="Peptide hormone">Peptide hormones</a></i>&#160;<span style="font-weight:bold;">·</span>  <i><a href="/wiki/Steroid_hormone" title="Steroid hormone">Steroid hormones</a></i>)</div>
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<div style="padding:0em 0.75em;"><a href="/wiki/Anterior_pituitary" title="Anterior pituitary">Anterior pituitary</a></div>
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<div style="padding:0em 0.25em"><a href="/wiki/Alpha_subunit_of_glycoprotein_hormones" title="Alpha subunit of glycoprotein hormones" class="mw-redirect">α</a> (<a href="/wiki/Follicle-stimulating_hormone" title="Follicle-stimulating hormone">FSH</a> <a href="/wiki/FSHB" title="FSHB">FSHB</a>, <a href="/wiki/Luteinizing_hormone" title="Luteinizing hormone">LH</a> <a href="/wiki/Luteinizing_hormone_beta_polypeptide" title="Luteinizing hormone beta polypeptide">LHB</a>, <a href="/wiki/Thyroid-stimulating_hormone" title="Thyroid-stimulating hormone">TSH</a> <a href="/wiki/TSHB" title="TSHB">TSHB</a>, <a href="/wiki/Chorionic_gonadotropin_alpha" title="Chorionic gonadotropin alpha">CGA</a>)&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Prolactin" title="Prolactin">Prolactin</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Proopiomelanocortin" title="Proopiomelanocortin">POMC</a> (<a href="/wiki/Corticotropin-like_intermediate_peptide" title="Corticotropin-like intermediate peptide">CLIP</a>, <a href="/wiki/Adrenocorticotropic_hormone" title="Adrenocorticotropic hormone">ACTH</a>, <a href="/wiki/Melanocyte-stimulating_hormone" title="Melanocyte-stimulating hormone">MSH</a>, <a href="/wiki/Endorphin" title="Endorphin">Endorphins</a>, <a href="/wiki/Lipotropin" title="Lipotropin">Lipotropin</a>)&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Growth_hormone" title="Growth hormone">GH</a></div>
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<div style="padding:0em 0.75em;"><a href="/wiki/Hypothalamic-pituitary-adrenal_axis" title="Hypothalamic-pituitary-adrenal axis" class="mw-redirect">Adrenal axis</a></div>
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<div style="padding:0em 0.25em"><b><a href="/wiki/Adrenal_gland#Adrenal_cortex" title="Adrenal gland">Adrenal cortex</a>:</b> <a href="/wiki/Aldosterone" title="Aldosterone">aldosterone</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Cortisol" title="Cortisol">cortisol</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Dehydroepiandrosterone" title="Dehydroepiandrosterone">DHEA</a><br />
<b><a href="/wiki/Adrenal_gland#Adrenal_medulla" title="Adrenal gland">Adrenal medulla</a>:</b> <a href="/wiki/Epinephrine" title="Epinephrine">epinephrine</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Norepinephrine" title="Norepinephrine">norepinephrine</a></div>
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<div style="padding:0em 0.75em;"><a href="/wiki/Hypothalamic-pituitary-thyroid_axis" title="Hypothalamic-pituitary-thyroid axis" class="mw-redirect">Thyroid axis</a></div>
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<div style="padding:0em 0.25em"><b><a href="/wiki/Thyroid" title="Thyroid">Thyroid</a>:</b> <a href="/wiki/Thyroid_hormone" title="Thyroid hormone">thyroid hormone</a> (<a href="/wiki/Triiodothyronine" title="Triiodothyronine">T<sub>3</sub></a> and <a href="/wiki/Thyroxine" title="Thyroxine">T<sub>4</sub></a>)&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Calcitonin" title="Calcitonin">calcitonin</a><br />
<b><a href="/wiki/Parathyroid" title="Parathyroid" class="mw-redirect">Parathyroid</a>:</b> <a href="/wiki/Parathyroid_hormone" title="Parathyroid hormone">PTH</a></div>
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<div style="padding:0em 0.75em;"><a href="/wiki/Hypothalamic-pituitary-gonadal_axis" title="Hypothalamic-pituitary-gonadal axis" class="mw-redirect">Gonadal axis</a></div>
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<p><b><a href="/wiki/Testis" title="Testis" class="mw-redirect">Testis</a>:</b> <a href="/wiki/Testosterone" title="Testosterone">testosterone</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Anti-M%C3%BCllerian_hormone" title="Anti-Müllerian hormone">AMH</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Activin_and_inhibin" title="Activin and inhibin">inhibin</a></p>
<p><b><a href="/wiki/Ovary" title="Ovary">Ovary</a>:</b> <a href="/wiki/Estradiol" title="Estradiol">estradiol</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Progesterone" title="Progesterone">progesterone</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Activin_and_inhibin" title="Activin and inhibin">activin and inhibin</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Relaxin" title="Relaxin">relaxin</a> (pregnancy)</p>
<b><a href="/wiki/Placenta" title="Placenta">Placenta</a>:</b> <a href="/wiki/Human_chorionic_gonadotropin" title="Human chorionic gonadotropin">hCG</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Human_placental_lactogen" title="Human placental lactogen">HPL</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Estrogen" title="Estrogen">estrogen</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Progesterone" title="Progesterone">progesterone</a></div>
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<div style="padding:0em 0.75em;">Islet-Acinar<br />
Axis</div>
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<div style="padding:0em 0.25em"><b><a href="/wiki/Pancreas" title="Pancreas">Pancreas</a>:</b> <a href="/wiki/Glucagon" title="Glucagon">glucagon</a>&#160;<span style="font-weight:bold;">·</span>  <strong class="selflink">insulin</strong>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Amylin" title="Amylin">amylin</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Somatostatin" title="Somatostatin">somatostatin</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Pancreatic_polypeptide" title="Pancreatic polypeptide">pancreatic polypeptide</a></div>
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<div style="padding:0em 0.75em;">Pineal gland</div>
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<div style="padding:0em 0.25em"><b><a href="/wiki/Pineal_gland" title="Pineal gland">Pineal gland</a>:</b> <a href="/wiki/Melatonin" title="Melatonin">melatonin</a></div>
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<th scope="row" class="navbox-group" style=";;">Non-end.<br />
glands</th>
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<p><b><a href="/wiki/Thymus" title="Thymus">Thymus</a>:</b> <a href="/wiki/Thymosin" title="Thymosin" class="mw-redirect">Thymosin</a> (<a href="/wiki/Thymosin_%CE%B11" title="Thymosin α1">Thymosin α1</a>, <a href="/wiki/Thymosin_beta" title="Thymosin beta" class="mw-redirect">Thymosin beta</a>)&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Thymopoietin" title="Thymopoietin">Thymopoietin</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Thymulin" title="Thymulin">Thymulin</a></p>
<p><i><a href="/wiki/Digestive_system" title="Digestive system" class="mw-redirect">Digestive system</a>:</i> <b><a href="/wiki/Stomach" title="Stomach">Stomach</a>:</b> <a href="/wiki/Gastrin" title="Gastrin">gastrin</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Ghrelin" title="Ghrelin">ghrelin</a>&#160;<span style="font-weight:bold;">·</span>  <b><a href="/wiki/Duodenum" title="Duodenum">Duodenum</a>:</b> <a href="/wiki/Cholecystokinin" title="Cholecystokinin">CCK</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Incretins" title="Incretins" class="mw-redirect">Incretins</a> (<a href="/wiki/Gastric_inhibitory_polypeptide" title="Gastric inhibitory polypeptide">GIP</a>, <a href="/wiki/Glucagon-like_peptide-1" title="Glucagon-like peptide-1">GLP-1</a>) &#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Secretin" title="Secretin">secretin</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Motilin" title="Motilin">motilin</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Vasoactive_intestinal_peptide" title="Vasoactive intestinal peptide">VIP</a>&#160;<span style="font-weight:bold;">·</span>  <b><a href="/wiki/Ileum" title="Ileum">Ileum</a>:</b> <a href="/wiki/Enteroglucagon" title="Enteroglucagon">enteroglucagon</a>&#160;<span style="font-weight:bold;">·</span> <a href="/wiki/Peptide_YY" title="Peptide YY">peptide YY</a>&#160;<span style="font-weight:bold;">·</span>  <b><a href="/wiki/Liver" title="Liver">Liver</a>/</b>other: <a href="/wiki/Insulin-like_growth_factor" title="Insulin-like growth factor">Insulin-like growth factor</a> (<a href="/wiki/Insulin-like_growth_factor_1" title="Insulin-like growth factor 1">IGF-1</a>, <a href="/wiki/Insulin-like_growth_factor_2" title="Insulin-like growth factor 2">IGF-2</a>)</p>
<p><b><a href="/wiki/Adipose_tissue" title="Adipose tissue">Adipose tissue</a>:</b> <a href="/wiki/Leptin" title="Leptin">leptin</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Adiponectin" title="Adiponectin">adiponectin</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Resistin" title="Resistin">resistin</a></p>
<p><b><a href="/wiki/Human_skeleton" title="Human skeleton">Skeleton</a>:</b> <a href="/wiki/Osteocalcin" title="Osteocalcin">Osteocalcin</a></p>
<p><b><a href="/wiki/Kidney" title="Kidney">Kidney</a>:</b> <i><a href="/wiki/Juxtaglomerular_apparatus" title="Juxtaglomerular apparatus">JGA</a></i> (<a href="/wiki/Renin" title="Renin">renin</a>)&#160;<span style="font-weight:bold;">·</span>  <i>peritubular cells</i> (<a href="/wiki/Erythropoietin" title="Erythropoietin">EPO</a>)&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Calcitriol" title="Calcitriol">calcitriol</a>&#160;<span style="font-weight:bold;">·</span>  <a href="/wiki/Prostaglandin" title="Prostaglandin">prostaglandin</a></p>
<b><a href="/wiki/Heart" title="Heart">Heart</a>:</b> <a href="/wiki/Natriuretic_peptide" title="Natriuretic peptide">Natriuretic peptide</a> (<a href="/wiki/Atrial_natriuretic_peptide" title="Atrial natriuretic peptide">ANP</a>, <a href="/wiki/Brain_natriuretic_peptide" title="Brain natriuretic peptide">BNP</a>)</div>
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<p><a href="/wiki/Template:Medicine_navs" title="Template:Medicine navs">M</a>: <a href="/wiki/Endocrine_system" title="Endocrine system">END</a></p>
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<p><a href="/wiki/Template:Endocrine_system_anatomy" title="Template:Endocrine system anatomy">anat</a>/<a href="/wiki/Template:Endocrinology_physiology" title="Template:Endocrinology physiology">phys</a>/<a href="/wiki/Template:Embryology_of_endocrine_system" title="Template:Embryology of endocrine system">devp</a>/<a href="/wiki/Template:Hormones" title="Template:Hormones">horm</a></p>
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<p><a href="/wiki/Template:Endocrine_pathology" title="Template:Endocrine pathology">noco</a>(<a href="/wiki/Template:Diabetes" title="Template:Diabetes">d</a>)/<a href="/wiki/Template:Congenital_endocrine_disorders" title="Template:Congenital endocrine disorders">cong</a>/<a href="/wiki/Template:Endocrine_gland_neoplasia" title="Template:Endocrine gland neoplasia">tumr</a>, <a href="/wiki/Template:Symptoms_concerning_nutrition,_metabolism_and_development" title="Template:Symptoms concerning nutrition, metabolism and development">sysi</a>/<a href="/wiki/Template:Eponymous_medical_signs_for_endocrinology,_nutrition,_and_metabolism" title="Template:Eponymous medical signs for endocrinology, nutrition, and metabolism">epon</a></p>
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<div>
<p><a href="/wiki/Template:Endocrine_system_procedures" title="Template:Endocrine system procedures">proc</a>, <a href="/wiki/ATC_code_A" title="ATC code A">drug</a> (<a href="/wiki/Template:Oral_hypoglycemics_and_insulin_analogs" title="Template:Oral hypoglycemics and insulin analogs">A10</a>/<a href="/wiki/Template:Pituitary_and_hypothalamic_hormones_and_analogues" title="Template:Pituitary and hypothalamic hormones and analogues">H1</a>/<a href="/wiki/Template:Corticosteroids" title="Template:Corticosteroids">H2</a>/<a href="/wiki/Template:Thyroid_therapy" title="Template:Thyroid therapy">H3</a>/<a href="/wiki/Template:Calcium_homeostasis" title="Template:Calcium homeostasis">H5</a>)</p>
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			<li class="interwiki-bar"><a href="//bar.wikipedia.org/wiki/Insulin" title="Insulin" lang="bar" hreflang="bar">Boarisch</a></li>
			<li class="interwiki-bs"><a href="//bs.wikipedia.org/wiki/Inzulin" title="Inzulin" lang="bs" hreflang="bs">Bosanski</a></li>
			<li class="interwiki-ca"><a href="//ca.wikipedia.org/wiki/Insulina" title="Insulina" lang="ca" hreflang="ca">Català</a></li>
			<li class="interwiki-cs"><a href="//cs.wikipedia.org/wiki/Inzulin" title="Inzulin" lang="cs" hreflang="cs">Česky</a></li>
			<li class="interwiki-da"><a href="//da.wikipedia.org/wiki/Insulin" title="Insulin" lang="da" hreflang="da">Dansk</a></li>
			<li class="interwiki-de"><a href="//de.wikipedia.org/wiki/Insulin" title="Insulin" lang="de" hreflang="de">Deutsch</a></li>
			<li class="interwiki-dv"><a href="//dv.wikipedia.org/wiki/%DE%87%DE%A8%DE%82%DE%B0%DE%90%DE%A8%DE%94%DE%AA%DE%8D%DE%A8%DE%82%DE%B0" title="އިންސިޔުލިން" lang="dv" hreflang="dv">ދިވެހިބަސް</a></li>
			<li class="interwiki-et"><a href="//et.wikipedia.org/wiki/Insuliin" title="Insuliin" lang="et" hreflang="et">Eesti</a></li>
			<li class="interwiki-el"><a href="//el.wikipedia.org/wiki/%CE%99%CE%BD%CF%83%CE%BF%CF%85%CE%BB%CE%AF%CE%BD%CE%B7" title="Ινσουλίνη" lang="el" hreflang="el">Ελληνικά</a></li>
			<li class="interwiki-es"><a href="//es.wikipedia.org/wiki/Insulina" title="Insulina" lang="es" hreflang="es">Español</a></li>
			<li class="interwiki-eo"><a href="//eo.wikipedia.org/wiki/Insulino" title="Insulino" lang="eo" hreflang="eo">Esperanto</a></li>
			<li class="interwiki-eu"><a href="//eu.wikipedia.org/wiki/Intsulina" title="Intsulina" lang="eu" hreflang="eu">Euskara</a></li>
			<li class="interwiki-fa"><a href="//fa.wikipedia.org/wiki/%D8%A7%D9%86%D8%B3%D9%88%D9%84%DB%8C%D9%86" title="انسولین" lang="fa" hreflang="fa">فارسی</a></li>
			<li class="interwiki-fr"><a href="//fr.wikipedia.org/wiki/Insuline" title="Insuline" lang="fr" hreflang="fr">Français</a></li>
			<li class="interwiki-ga"><a href="//ga.wikipedia.org/wiki/Inslin" title="Inslin" lang="ga" hreflang="ga">Gaeilge</a></li>
			<li class="interwiki-gl"><a href="//gl.wikipedia.org/wiki/Insulina" title="Insulina" lang="gl" hreflang="gl">Galego</a></li>
			<li class="interwiki-ko"><a href="//ko.wikipedia.org/wiki/%EC%9D%B8%EC%8A%90%EB%A6%B0" title="인슐린" lang="ko" hreflang="ko">한국어</a></li>
			<li class="interwiki-hi"><a href="//hi.wikipedia.org/wiki/%E0%A4%87%E0%A4%A8%E0%A5%8D%E0%A4%B8%E0%A5%81%E0%A4%B2%E0%A4%BF%E0%A4%A8" title="इन्सुलिन" lang="hi" hreflang="hi">हिन्दी</a></li>
			<li class="interwiki-hr"><a href="//hr.wikipedia.org/wiki/Inzulin" title="Inzulin" lang="hr" hreflang="hr">Hrvatski</a></li>
			<li class="interwiki-id"><a href="//id.wikipedia.org/wiki/Insulin" title="Insulin" lang="id" hreflang="id">Bahasa Indonesia</a></li>
			<li class="interwiki-is"><a href="//is.wikipedia.org/wiki/Ins%C3%BAl%C3%ADn" title="Insúlín" lang="is" hreflang="is">Íslenska</a></li>
			<li class="interwiki-it"><a href="//it.wikipedia.org/wiki/Insulina" title="Insulina" lang="it" hreflang="it">Italiano</a></li>
			<li class="interwiki-he"><a href="//he.wikipedia.org/wiki/%D7%90%D7%99%D7%A0%D7%A1%D7%95%D7%9C%D7%99%D7%9F" title="אינסולין" lang="he" hreflang="he">עברית</a></li>
			<li class="interwiki-jv"><a href="//jv.wikipedia.org/wiki/Insulin" title="Insulin" lang="jv" hreflang="jv">Basa Jawa</a></li>
			<li class="interwiki-pam"><a href="//pam.wikipedia.org/wiki/Insulin" title="Insulin" lang="pam" hreflang="pam">Kapampangan</a></li>
			<li class="interwiki-kk"><a href="//kk.wikipedia.org/wiki/%D0%98%D0%BD%D1%81%D1%83%D0%BB%D0%B8%D0%BD" title="Инсулин" lang="kk" hreflang="kk">Қазақша</a></li>
			<li class="interwiki-ku"><a href="//ku.wikipedia.org/wiki/%C3%8Ensul%C3%AEn" title="Însulîn" lang="ku" hreflang="ku">Kurdî</a></li>
			<li class="interwiki-la"><a href="//la.wikipedia.org/wiki/Insulinum" title="Insulinum" lang="la" hreflang="la">Latina</a></li>
			<li class="interwiki-lv"><a href="//lv.wikipedia.org/wiki/Insul%C4%ABns" title="Insulīns" lang="lv" hreflang="lv">Latviešu</a></li>
			<li class="interwiki-lt"><a href="//lt.wikipedia.org/wiki/Insulinas" title="Insulinas" lang="lt" hreflang="lt">Lietuvių</a></li>
			<li class="interwiki-hu"><a href="//hu.wikipedia.org/wiki/Inzulin" title="Inzulin" lang="hu" hreflang="hu">Magyar</a></li>
			<li class="interwiki-mk"><a href="//mk.wikipedia.org/wiki/%D0%98%D0%BD%D1%81%D1%83%D0%BB%D0%B8%D0%BD" title="Инсулин" lang="mk" hreflang="mk">Македонски</a></li>
			<li class="interwiki-ml"><a href="//ml.wikipedia.org/wiki/%E0%B4%87%E0%B5%BB%E0%B4%B8%E0%B5%81%E0%B4%B2%E0%B4%BF%E0%B5%BB" title="ഇൻസുലിൻ" lang="ml" hreflang="ml">മലയാളം</a></li>
			<li class="interwiki-ms"><a href="//ms.wikipedia.org/wiki/Insulin" title="Insulin" lang="ms" hreflang="ms">Bahasa Melayu</a></li>
			<li class="interwiki-my"><a href="//my.wikipedia.org/wiki/%E1%80%A1%E1%80%84%E1%80%BA%E1%80%86%E1%80%B0%E1%80%9C%E1%80%84%E1%80%BA" title="အင်ဆူလင်" lang="my" hreflang="my">မြန်မာဘာသာ</a></li>
			<li class="interwiki-nl"><a href="//nl.wikipedia.org/wiki/Insuline" title="Insuline" lang="nl" hreflang="nl">Nederlands</a></li>
			<li class="interwiki-ne"><a href="//ne.wikipedia.org/wiki/%E0%A4%87%E0%A4%A8%E0%A5%8D%E0%A4%B8%E0%A5%81%E0%A4%B2%E0%A4%BF%E0%A4%A8" title="इन्सुलिन" lang="ne" hreflang="ne">नेपाली</a></li>
			<li class="interwiki-ja"><a href="//ja.wikipedia.org/wiki/%E3%82%A4%E3%83%B3%E3%82%B9%E3%83%AA%E3%83%B3" title="インスリン" lang="ja" hreflang="ja">日本語</a></li>
			<li class="interwiki-no"><a href="//no.wikipedia.org/wiki/Insulin" title="Insulin" lang="no" hreflang="no">‪Norsk (bokmål)‬</a></li>
			<li class="interwiki-nn"><a href="//nn.wikipedia.org/wiki/Insulin" title="Insulin" lang="nn" hreflang="nn">‪Norsk (nynorsk)‬</a></li>
			<li class="interwiki-oc"><a href="//oc.wikipedia.org/wiki/Insulina" title="Insulina" lang="oc" hreflang="oc">Occitan</a></li>
			<li class="interwiki-pnb"><a href="//pnb.wikipedia.org/wiki/%D8%A7%D9%86%D8%B3%D9%88%D9%84%DB%8C%D9%86" title="انسولین" lang="pnb" hreflang="pnb">پنجابی</a></li>
			<li class="interwiki-ps"><a href="//ps.wikipedia.org/wiki/%D8%A7%D9%86%D8%B3%D9%88%D9%84%D9%8A%D9%86" title="انسولين" lang="ps" hreflang="ps">پښتو</a></li>
			<li class="interwiki-pl"><a href="//pl.wikipedia.org/wiki/Insulina" title="Insulina" lang="pl" hreflang="pl">Polski</a></li>
			<li class="interwiki-pt"><a href="//pt.wikipedia.org/wiki/Insulina" title="Insulina" lang="pt" hreflang="pt">Português</a></li>
			<li class="interwiki-ro"><a href="//ro.wikipedia.org/wiki/Insulin%C4%83" title="Insulină" lang="ro" hreflang="ro">Română</a></li>
			<li class="interwiki-ru"><a href="//ru.wikipedia.org/wiki/%D0%98%D0%BD%D1%81%D1%83%D0%BB%D0%B8%D0%BD" title="Инсулин" lang="ru" hreflang="ru">Русский</a></li>
			<li class="interwiki-sq"><a href="//sq.wikipedia.org/wiki/Insulina" title="Insulina" lang="sq" hreflang="sq">Shqip</a></li>
			<li class="interwiki-simple"><a href="//simple.wikipedia.org/wiki/Insulin" title="Insulin" lang="simple" hreflang="simple">Simple English</a></li>
			<li class="interwiki-sk"><a href="//sk.wikipedia.org/wiki/Inzul%C3%ADn" title="Inzulín" lang="sk" hreflang="sk">Slovenčina</a></li>
			<li class="interwiki-sl"><a href="//sl.wikipedia.org/wiki/Insulin" title="Insulin" lang="sl" hreflang="sl">Slovenščina</a></li>
			<li class="interwiki-ckb"><a href="//ckb.wikipedia.org/wiki/%D8%A6%DB%95%D9%86%D8%B3%DB%86%D9%84%DB%8C%D9%86" title="ئەنسۆلین" lang="ckb" hreflang="ckb">کوردی</a></li>
			<li class="interwiki-sr"><a href="//sr.wikipedia.org/wiki/%D0%98%D0%BD%D1%81%D1%83%D0%BB%D0%B8%D0%BD" title="Инсулин" lang="sr" hreflang="sr">Српски / Srpski</a></li>
			<li class="interwiki-su"><a href="//su.wikipedia.org/wiki/Insulin" title="Insulin" lang="su" hreflang="su">Basa Sunda</a></li>
			<li class="interwiki-fi"><a href="//fi.wikipedia.org/wiki/Insuliini" title="Insuliini" lang="fi" hreflang="fi">Suomi</a></li>
			<li class="interwiki-sv"><a href="//sv.wikipedia.org/wiki/Insulin" title="Insulin" lang="sv" hreflang="sv">Svenska</a></li>
			<li class="interwiki-ta"><a href="//ta.wikipedia.org/wiki/%E0%AE%87%E0%AE%A9%E0%AF%8D%E0%AE%9A%E0%AF%81%E0%AE%B2%E0%AE%BF%E0%AE%A9%E0%AF%8D" title="இன்சுலின்" lang="ta" hreflang="ta">தமிழ்</a></li>
			<li class="interwiki-th"><a href="//th.wikipedia.org/wiki/%E0%B8%AD%E0%B8%B4%E0%B8%99%E0%B8%8B%E0%B8%B9%E0%B8%A5%E0%B8%B4%E0%B8%99" title="อินซูลิน" lang="th" hreflang="th">ไทย</a></li>
			<li class="interwiki-tr"><a href="//tr.wikipedia.org/wiki/%C4%B0ns%C3%BClin" title="İnsülin" lang="tr" hreflang="tr">Türkçe</a></li>
			<li class="interwiki-uk"><a href="//uk.wikipedia.org/wiki/%D0%86%D0%BD%D1%81%D1%83%D0%BB%D1%96%D0%BD" title="Інсулін" lang="uk" hreflang="uk">Українська</a></li>
			<li class="interwiki-ur"><a href="//ur.wikipedia.org/wiki/%D8%AC%D8%B2%DB%8C%D8%B1%DB%8C%D9%86" title="جزیرین" lang="ur" hreflang="ur">اردو</a></li>
			<li class="interwiki-vi"><a href="//vi.wikipedia.org/wiki/Insulin" title="Insulin" lang="vi" hreflang="vi">Tiếng Việt</a></li>
			<li class="interwiki-yi"><a href="//yi.wikipedia.org/wiki/%D7%90%D7%99%D7%A0%D7%A1%D7%95%D7%9C%D7%99%D7%9F" title="אינסולין" lang="yi" hreflang="yi">ייִדיש</a></li>
			<li class="interwiki-zh"><a href="//zh.wikipedia.org/wiki/%E8%83%B0%E5%B2%9B%E7%B4%A0" title="胰岛素" lang="zh" hreflang="zh">中文</a></li>
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